Clinical trial NCT03267186
Conditions: Acute Biphenotypic Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Hematopoietic Cell Transplantation Recipient
Sponsor: Andrew Rezvani
Start date: 2017-09-12; Completion date: 2021-04-30
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ibrutinib works in preventing acute leukemia in patients after reduced-intensity conditioning and stem cell transplant. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To reduce the incidence of relapse at 18 months after reduced-intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) in blast crisis from a historical baseline of 45% to 25%, using ibrutinib maintenance therapy.

SECONDARY OBJECTIVES:

I. To study the incidence and severity of post-transplant complications in subjects receiving ibrutinib maintenance after allogeneic HCT.

II. To study the incidence of infectious complications in subjects receiving maintenance ibrutinib after allogeneic HCT.

III. To study the impact of ibrutinib maintenance on minimal residual disease after RIC and allogeneic HCT.

IV. To study the impact of maintenance ibrutinib on immune reconstitution and alloreactivity after allogeneic HCT, specifically on Th1/ Th2 polarization, T follicular cell number, T and B cell repertoire, serum immunoglobulin levels, and alloantibody formation.

OUTLINE:

Beginning 60-90 days after allogeneic HCT, patients receive ibrutinib orally (PO) once daily (QD) for up to 18 months post-transplant in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.

Arms: arm 1: Beginning 60-90 days after allogeneic HCT, patients receive ibrutinib PO QD for up to 18 months post-transplant in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ibrutinib intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_001.pdf: 
A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and Allogeneic 
Hematopoietic Cell Transplantation for Acute Leukemia 
 
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A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning 
and Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Dr 
Stanford, CA 94305 
Protocol Director and Lead Principal Investigator   
Andrew R Rezvani, MD  
Stanford University 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Telephone:  650-725-4077;  Fax:  650-725-8950 
arezvani@stanford.edu  
Coordinating Center Sub-Investigators 
David Miklos, MD, PhD  
Stanford University 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Tel:   650-725-4959;  Fax:  650-498-6159 
Email:  dmiklos@stanford.edu 
Principal Investigators 
Leyla Shune, MD  
The University of Kansas Medical Center 
 
Westwood, KS 66205 
Tel:  
 
Email: lshune@kumc.edu 
Biostatistician 
, PhD  
Stanford University 
HRP Redwood Building, 
 
150 Governor's Lane 
Stanford, CA 94305 
Tel:  
;  Fax:  
 
Email:  
@stanford.edu  
Lead Study Coordinator 
, RN  
Stanford University 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Tel:  
;  Fax:  
 
@stanford.edu   
Version Date:  23 November 2020 
 
NCT03267186 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ................................................................................................. 4 
SCHEMA ......................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  ......................................... 7 
1. OBJECTIVES ........................................................................................................... 8 
1.1. PRIMARY OBJECTIVE ............................................................................................. 8 
1.2. SECONDARY OBJECTIVES ...................................................................................... 8 
2. BACKGROUND ........................................................................................................ 8 
2.1 STUDY DISEASE ..................................................................................................... 8 
2.2 STUDY AGENT/DEVICE/PROCEDURE ........................................................................ 8 
2.3 RATIONALE .......................................................................................................... 10 
2.4 STUDY DESIGN .................................................................................................... 10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ...................... 10 
3.1 INCLUSION CRITERIA ............................................................................................ 10 
3.2 EXCLUSION CRITERIA ........................................................................................... 12 
3.3 INFORMED CONSENT PROCESS ............................................................................. 13 
3.4 STUDY TIMELINE .................................................................................................. 13 
4. TREATMENT PLAN ............................................................................................... 14 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............. 15 
4.2 CRITERIA FOR REMOVAL FROM STUDY ................................................................... 18 
4.3 ALTERNATIVES ..................................................................................................... 18 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION.................. 18 
5.1  INVESTIGATIONAL AGENT/DEVICE/PROCEDURE ...................................................... 18 
5.2 AVAILABILITY ....................................................................................................... 23 
5.3 AGENT ORDERING ................................................................................................ 23 
5.4 AGENT ACCOUNTABILITY ...................................................................................... 23 
6. DOSE MODIFICATIONS ........................................................................................ 24 
6.1 TREATMENT DISCONTINUATION ............................................................................. 23 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ...................................... 26 
7.1 POTENTIAL ADVERSE EVENTS ............................................................................... 27 
7.2 ADVERSE EVENT REPORTING ................................................................................ 27 
8. CORRELATIVE/SPECIAL STUDIES ..................................................................... 32 
9. STUDY CALENDAR ............................................................................................... 36 
10. MEASUREMENT .................................................................................................. 37 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES ................................................ 37 
11. REGULATORY CONSIDERATIONS .................................................................... 38 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ................................................................. 38 
11.2 DATA AND SAFETY MONITORING PLAN ................................................................. 38 


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11.3 DATA MANAGEMENT PLAN .................................................................................. 38 
11.4 CONFIDENTIALITY ............................................................................................... 39 
11.5 REPORTING MECHANISMS ................................................................................... 40 
12. STATISTICAL CONSIDERATIONS...................................................................... 40 
12.1 STATISTICAL DESIGN .......................................................................................... 40 
12.2 INTERIM ANALYSES ............................................................................................. 41 
12.3 ANALYSIS POPULATION ....................................................................................... 41 
12.4 ACCRUAL ESTIMATES ......................................................................................... 41 
13. REFERENCES ...................................................................................................... 43 
APPENDICES ............................................................................................................... 45 
APPENDIX A:  PRE-TRANSPLANT ELIGIBLITY CHECKLIST .................................................. 45 
APPENDIX B:  SECONDARY CRITERIA TO CONTINUE TO IBRUTINIB TREATMENT .................. 47 
APPENDIX C:  GRADING OF ACUTE GRAFT-VS-HOST DISEASE ......................................... 50 
APPENDIX D:  ASSESSMENT OF CHRONIC GRAFT-VS-HOST DISEASE ............................... 51 
APPENDIX E:  INHIBITORS AND INDUCERS OF CYP3A ...................................................... 57 
APPENDIX F:  CHILD-PUGH SCORING CRITERIA .............................................................. 59 
 
Table of Tables 
Table 1:  Most frequently reported treatment-emergent adverse events (TEAEs)  .. 21 
Table 2:  Ibrutinib Dose Modifications ...................................................................... 25 
Table 3:  Schedule of correlative laboratory studies ................................................ 33 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
A Phase 2 Study of Ibrutinib Maintenance After 
Reduced-Intensity Conditioning and Allogeneic 
Hematopoietic Cell Transplantation for Acute Leukemia 
STUDY PHASE 
Phase 2 
INDICATION 
Prevention of relapse in subjects with acute leukemias 
undergoing reduced-intensity conditioning and allogeneic 
hematopoietic cell transplantation 
INVESTIGATIONAL 
PRODUCT 
Ibrutinib 
PRIMARY 
OBJECTIVE(S) 
To reduce the incidence of relapse at 18 months after RIC 
and allogeneic HCT for AML, ALL, and CML in blast crisis 
from 45% to 25% 
SECONDARY 
OBJECTIVE(S) 
• To study the incidence and severity of post-transplant 
complications in subjects receiving ibrutinib maintenance 
after allogeneic HCT. 
• To study the incidence of infectious complications in 
subjects receiving maintenance ibrutinib after allogeneic 
HCT. 
• To study the impact of ibrutinib maintenance on minimal 
residual disease after RIC and allogeneic HCT. 
• To study the impact of maintenance ibrutinib on immune 
reconstitution and alloreactivity after allogeneic HCT, 
specifically on Th1/Th2 polarization, T follicular cell 
number, T- and B-cell repertoire, serum immunoglobulin 
levels, and alloantibody formation. 
INCLUSION CRITERIA • Diagnosis of acute myeloid leukemia (AML), acute 
biphenotypic leukemia, or acute lymphoblastic leukemia 
(ALL).  CML transformed to blast crisis is eligible. 
• Planned allogeneic HCT using FLU/MEL or FLU/BU 
conditioning (regimens defined in protocol). 
• Planned GvHD prophylaxis consisting of TAC/MTX or 
TAC/SRL (regimens defined in protocol). 
• HLA-identical sibling donor, HLA-matched unrelated 
donor, or donor mismatched at 1 HLA allele or antigen. 
• Less than or equal to 5% blasts on bone marrow 
examination within 60 days of starting conditioning. 
• Age ≥ 18 years and ≤ 70 years. 
• Able to give informed consent. 


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EXCLUSION 
CRITERIA 
• Active involvement of the central nervous system with 
malignancy (previous CNS involvement is allowed if 
clearance of CNS disease has been documented prior to 
enrollment) 
• Pregnant or breastfeeding 
• Karnofsky Performance Status < 60% 
• Active leukemia (> 5% leukemic blasts in peripheral 
blood or bone marrow) 
• Non-hematologic malignancy with a life expectancy of 
< 5 years 
• Known history of human immunodeficiency virus (HIV) or 
active hepatitis C virus (HCV) or hepatitis B virus (HBV) 
infection.  Subjects who are positive for hepatitis B core 
antibody or hepatitis B surface antigen must have a 
negative polymerase chain reaction (PCR) result before 
enrollment.  Those who are PCR-positive will be 
excluded. 
• Known bleeding disorders (eg, von Willebrand’s disease) 
or hemophilia. 
• History of other malignancies, except:  
o Malignancy treated with curative intent and with no 
known active disease present for ≥ 3 years before the 
first dose of study drug and felt to be at low risk for 
recurrence by treating physician. 
o Adequately treated non-melanoma skin cancer or 
lentigo maligna without evidence of disease. 
o Adequately treated carcinoma in situ without evidence 
of disease.  
TREATMENT 
SUMMARY 
Subjects will be treated with ibrutinib 420 mg orally once 
daily, starting between Day +60 and Day +90 after 
allogeneic HCT and continuing until 18 months 
post-transplant 
SAMPLE SIZE  
50 subjects enrolled and treated 
STATISTICAL 
CONSIDERATIONS 
Screening and enrollment of 50 subjects will provide 
84% power to detect a decrease in the incidence of relapse 
at 18 months post-transplant from 45% to 25% 
 


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SCHEMA 
 
 
 
Reduced-Intensity Conditioning Regimens: 
Fludarabine/Busulfan (FLU/BU) 
- 
Fludarabine (120 to 180 mg/m2) 
- 
Busulfan (≤ 8 mg/kg PO or 6.4 mg/kg IV) 
 
Fludarabine/Melphalan (FLU/MEL) 
- 
Fludarabine (120 to 180 mg/mg2) 
- 
Melphalan (≤ 150 mg/m2) 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ALL 
Acute lymphoblastic leukemia 
AE 
Adverse event 
AML 
Acute myeloid leukemia 
BCR 
B-cell receptor 
BTK 
Bruton’s tyrosine kinase 
BU 
Busulfan 
CBC 
Complete blood count 
CLL 
Chronic lymphocytic leukemia 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
FLU 
Fludarabine 
GvHD 
Graft-vs-host disease 
GI 
Gastrointestinal 
HCT 
Hematopoietic cell transplantation 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HTN 
Hypertensions 
IRB 
Institutional Review Board 
ITK 
Interleukin-2-inducible T-cell kinase 
IV 
Intravenous 
MCL 
Mantle cell lymphoma 
MEL 
Melphalan 
MTX 
Methotrexate 
NRM 
Non-relapse mortality 
OS 
Overall survival  
PLT 
Platelet 
PFS 
Progression-free survival  
PR 
Partial response 
RIC 
Reduced-intensity conditioning 
RR 
Response rate 
SAE 
Serious adverse event 
SRL 
Sirolimus 
TAC 
Tacrolimus 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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1. 
OBJECTIVES 
1.1 
Primary Objective  
• To reduce the incidence of relapse at 18 months after RIC and allogeneic HCT 
for AML, ALL, and CML in blast crisis from a historical baseline of 45% to 25%, 
using ibrutinib maintenance therapy. 
1.2 
Secondary Objectives 
 
• To study the incidence and severity of post-transplant complications in subjects 
receiving ibrutinib maintenance after allogeneic HCT. 
• To study the incidence of infectious complications in subjects receiving 
maintenance ibrutinib after allogeneic HCT. 
• To study the impact of ibrutinib maintenance on minimal residual disease after 
RIC and allogeneic HCT. 
• To study the impact of maintenance ibrutinib on immune reconstitution and 
alloreactivity after allogeneic HCT, specifically on Th1/Th2 polarization, T 
follicular cell number, T- and B-cell repertoire, serum immunoglobulin levels, and 
alloantibody formation. 
2. 
BACKGROUND 
2.1 
Allogeneic hematopoietic cell transplantation in acute leukemia 
Allogeneic HCT is frequently performed with curative intent in patients with AML and 
ALL.  Reduced-intensity conditioning is utilized in older patients, or in those with 
significant medical comorbidities, in order to reduce the risk of regimen-related toxicity 
and mortality.  However, leukemia relapse after RIC and allogeneic HCT is the most 
common cause of treatment failure in this patient population.  Patients receiving RIC are 
generally thought to have a higher risk of relapse compared to those receiving 
high-dose conditioning (1, 2).  The incidence of post-transplant relapse in this setting is 
approximately 45% with current transplant approaches (1-6).  
2.2 
Ibrutinib 
Ibrutinib is a first-in-class, potent, orally-administered, covalently-binding inhibitor of 
Bruton’s tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor 
(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:  1) mantle cell lymphoma (MCL) in 
patients who have received at least one prior therapy based on overall response rate;   
2) chronic lymphocytic leukemia (CLL) in patients who have received at least one prior 
therapy;   3) CLL in patients with 17p deletion;  and 4) Waldenström macroglobulinemia.  
Ibrutinib is currently under investigation in various indications.  It is not currently 
approved as a maintenance therapy for acute leukemia following allogeneic HCT, so 
this clinical trial requires an Investigational New Drug (IND) application. 
B-cells are lymphocytes with multiple functions in the immune response, including 
antigen presentation, antibody production, and cytokine release.  B-cells express cell 


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surface immunoglobulins comprising the B-cell receptor (BCR), which is activated by 
binding to antigen.  Antigen binding induces receptor aggregation and the clustering and 
activation of multiple tyrosine kinases, which in turn activate further downstream 
signaling pathways (7).  
The process of B-cell maturation, including immunoglobulin chain rearrangement and 
somatic mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL 
result from mutations and translocations acquired during normal B-cell development (8).  
Several lines of evidence suggest that signaling through the BCR is necessary to 
sustain the viability of B-cell malignancies.   
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic 
disease X-linked immunodeficiency, both caused by a mutation in the BTK gene.  These 
genetic diseases are characterized by reduced BCR signaling and a failure to generate 
mature B-cells.  The BTK protein is expressed in most hematopoietic cells with the 
exception of T-cells and natural killer cells, but the selective effect of BTK mutations 
suggests that its primary functional role is in antigen receptor signaling in B-cells (9).  
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated 
from the plasma after oral administration, once daily dosing with ibrutinib is adequate to 
sustain maximal pharmacodynamic activity for 24 hours post-dose at dose levels 
≥ 2.5 mg/kg.  In Study PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 
12.5 mg/kg/day cohorts and for the 560 mg continuous dosing cohort, were all above 
90% at either 4 or 24 hours after drug administration. 
Pre-clinical data suggest that ibrutinib may have direct anti-tumor activity in AML.  The 
drug’s target, BTK, is constitutively activated in many forms of AML, and BTK inhibition 
with ibrutinib prevents AML blast proliferation in pre-clinical studies (10).  Ibrutinib has 
also been shown to inhibit SDF1/CXCR4 interactions, thus interfering with the migration 
of leukemic cells and potentially rendering them more vulnerable to cytotoxic 
chemotherapy or graft--vs-leukemia effects by separating the leukemic cells from their 
protected niche (11).  Given the activity of ibrutinib against B-cells, this compound is 
also under active investigation for its anti-tumor effects in acute B-lymphoblastic 
leukemias (12). 
Recent studies show that B-cells are key mediators of chronic GvHD.  Dysfunctional 
B-cells have been identified in chronic GvHD, where patients have a relatively higher 
number of activated memory B-cells, higher levels of B-cell-activating factor of the tumor 
necrosis family (BAFF), and donor-derived alloantibodies (13).  It has been 
demonstrated that pathogenic antibody deposition occurs in human chronic GvHD, and 
a network of alloreactive T-helper cells, including Th1, Th2, Th17 and Tfh (T-follicular 
helper) cells infiltrate tissues and produce effector cytokines thereby causing antibody 
deposition and tissue fibrosis, similar to autoimmunity.  In addition, genetic studies 
confirmed that ITK and BTK are independently critical for chronic GvHD.  Ibrutinib, 
which hits both targets, showed effectiveness in both T-cell-driven and 
alloantibody-driven chronic GvHD models.  Ibrutinib treatment delayed progression, 
improved survival and ameliorated clinical and pathological manifestations in mouse 
models of sclerodermatous and alloantibody-driven chronic GvHD (14). 


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2.3 
Rationale 
This study is designed to test the hypothesis that ibrutinib maintenance therapy will 
reduce the incidence of post-transplant relapse in subjects receiving RIC and allogeneic 
HCT for AML and ALL.  The rationale for the use of ibrutinib in this setting is twofold:  
ibrutinib may have direct anti-tumor effects against both AML and ALL, as described 
above; and ibrutinib may potentiate the immunologic graft--vs-leukemia effect driven by 
donor T-cells after allogeneic HCT.  In addition to the BTK-mediated effects of ibrutinib, 
the compound is known to inhibit ITK, a tyrosine kinase which plays a central role in 
T-cell differentiation (15).  By inhibiting ITK, ibrutinib may drive donor T-cells toward a 
Th1 phenotype, which is hypothesized to generate more effective graft--vs-leukemia 
reactions. 
2.4 
Study Design 
This is a treatment, single-group, single-intervention, open-label, non-randomized 
efficacy trial. 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Refer to the Participant Eligibility Checklists in Appendices A & B.  Eligibility will 
be assessed initially before allogeneic HCT, and second confirmation of eligibility 
will be assessed prior to the administration of ibrutinib, between Day +60 and 
Day +90 after allogeneic HCT. 
3.1 
Inclusion Criteria  
3.1.1 Inclusion Criteria for enrollment (pre-transplant) 
• Diagnosis of acute myeloid leukemia (AML), acute biphenotypic leukemia, or 
acute lymphoblastic leukemia (ALL).  CML transformed to blast crisis is eligible. 
• Planned allogeneic HCT using FLU/MEL or FLU/BU conditioning (regimens 
defined below). 
• Planned GvHD prophylaxis consisting of TAC/MTX or TAC/SRL (regimens 
defined below). 
• HLA-identical sibling donor, HLA-matched unrelated donor, or donor mismatched 
at 1 HLA allele or antigen. 
• Less than or equal to 5% blasts on bone marrow examination within 60 days of 
starting conditioning. 
• Age ≥ 18 years and ≤ 70 years. 
• Able to give informed consent. 
Subjects will be eligible if their planned conditioning regimen for allogeneic HCT 
consists of one of the two following standard reduced-intensity conditioning regimens: 
• FLU/MEL:  Fludarabine 120 to 180 mg/m2;  melphalan ≤ 150 mg/m2 
• FLU/BU:  Fludarabine 120 to 180 mg/m2;  busulfan ≤ 8 mg/kg orally or 
≤ 6.4 mg/kg intravenously 


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Subjects will be eligible if their planned post-grafting immunosuppression consists of 
one of the two following regimens: 
• TAC/MTX:  Tacrolimus (oral or intravenous) and intravenous methotrexate 
administered according to institutional standard practice. 
• TAC/SRL:  Tacrolimus (oral or intravenous) and oral sirolimus, administered 
according to institutional standards of care. 
These two regimens of post-grafting immunosuppression have been shown to produce 
equivalent rates of GvHD, relapse-free survival, and GvHD-free survival in a 
prospective, randomized controlled trial (16), and we thus view them as equivalent for 
the purposes of this clinical trial.  Immunosuppressant doses and taper schedules will 
be adjusted based on institutional standard practice and clinical factors, at the discretion 
of the attending physician, as in previous clinical trials of these regimens (16). 
3.1.2 Inclusion criteria (prior to ibrutinib administration) 
• Age ≥ 18 years 
• Adequate hematologic function, defined as ANC > 0.75 x 109/L;  platelet count 
> 50 x 109/L;  and hemoglobin > 8.0 g/dL without transfusion or growth-factor 
support for at least 7 days prior to screening (with the exception of pegylated 
G-CSF and darbopoietin, which require at least 14 days of abstinence prior to 
screening) 
• Adequate hepatic and renal function, as defined by serum AST and ALT 
≤ 3.0 x upper limit of normal (ULN);  estimated creatinine clearance ≥ 30 mL/min 
via Cockroft-Gault formula;  nd bilirubin ≤ 1.5 x ULN (unless elevated bilirubin is 
due to Gilbert’s syndrome or of non-hepatic origin) 
• Adequate coagulation studies, defined as PT/INR and PTT (aPTT) ≤ 1.5 x ULN 
• Female subjects who are of non-reproductive potential (ie, post-menopausal by 
history - no menses for ≥ 1 year;  OR history of hysterectomy;  OR history of 
bilateral tubal ligation; OR history of bilateral oophorectomy).  Female subjects of 
childbearing potential must have a negative serum pregnancy test upon 
screening. 
• Male and female subjects who agree to use both a highly effective method of 
birth control (eg, implants;  injectables;  combined oral contraceptives;  some 
intrauterine devices [IUDs];  sexual abstinence;  or sterilized partner) and a 
barrier method (eg, condoms;  vaginal ring;  sponge;  etc) during the period of 
therapy and for 30 days after the last dose of study drug for females and 90 days 
after the last dose of the study drug for males. 
• Between Day +60 and Day +90 after allogeneic HCT 


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3.2 
Exclusion Criteria  
3.2.1 Exclusion Criteria for enrollment (pre-transplant) 
• Active involvement of the central nervous system with malignancy (previous CNS 
involvement is allowed if clearance of CNS disease has been documented prior 
to enrollment) 
• Pregnant or breastfeeding 
• Karnofsky Performance Status < 60% 
• Active leukemia (> 5% leukemic blasts in peripheral blood or bone marrow) 
• Non-hematologic malignancy with a life expectancy of < 5 years 
• Known history of human immunodeficiency virus (HIV) or active hepatitis C virus 
(HCV) or hepatitis B virus (HBV) infection.  Subjects who are positive for 
hepatitis B core antibody or hepatitis B surface antigen must have a negative 
polymerase chain reaction (PCR) result before enrollment.  Those who are 
PCR-positive will be excluded. 
• Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia. 
• History of other malignancies, except:  
o Malignancy treated with curative intent and with no known active disease 
present for ≥ 3 years before the first dose of study drug and felt to be at low 
risk for recurrence by treating physician. 
o Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
o Adequately treated carcinoma in situ without evidence of disease.  
3.2.2 Exclusion Criteria (prior to ibrutinib administration) 
• Active and uncontrolled acute GvHD Grades III or IV 
• Use of secondary therapy for acute GvHD at any time (defined as any systemic 
therapy intended to treat acute GvHD besides corticosteroids) 
• Requirement for anticoagulation with warfarin or other Vitamin K antagonists 
(concomitant use of other anticoagulants is permitted) 
• Relapsed leukemia (> 5% leukemic blasts in peripheral blood or bone marrow 
after allogeneic HCT) 
• Karnofsky Performance Status < 60% 
• Chemotherapy ≤ 21 days prior to first administration of study treatment and/or 
monoclonal antibody ≤ 6 weeks prior to first administration of study treatment 
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study 
drug. 
• Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the 
New York Heart Association Functional Classification; or a history of myocardial 
infarction, unstable angina, or acute coronary syndrome within 6 months prior to 
randomization. 


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• History of stroke or intracranial hemorrhage within 6 months prior to screening 
• Any life-threatening illness, medical condition, or organ system dysfunction that, 
in the investigator’s opinion, could compromise the subject’s safety or put the 
study outcomes at undue risk. 
• Major surgery within 4 weeks of first dose of study drug. 
• Any uncontrolled active systemic infection. 
• Unresolved toxicities from prior anti-cancer therapy, defined as having not 
resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), 
Grade ≤ 1, or to the levels dictated in the inclusion/exclusion criteria with the 
exception of alopecia 
• Unable to swallow capsules or malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease or ulcerative colitis, or partial or 
complete bowel obstruction 
• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor 
(see Appendix E). 
• Unwilling or unable to participate in all required study evaluations and 
procedures. 
• Unable to understand the purpose and risks of the study and to provide a signed 
and dated informed consent form (ICF) and authorization to use protected health 
information (in accordance with national and local subject privacy regulations). 
• Currently active, clinically significant hepatic impairment 
(Child-Pugh Class B or C) 
• Lactating or pregnant 
• Uncontrolled cardiac arrhythmias 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any 
study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained 
in the medical record or research file.  
3.4 
Study Timeline 
Primary Completion: 
The study is expected to complete accrual within 1 year, and to complete treatment 
within 2 years of opening. 
Study Completion: 
The study is expected to be completed within 2.5 years of opening. 


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4. 
TREATMENT PLAN 
Subjects will be assessed for eligibility and enrolled prior to allogeneic HCT, using the 
pre-transplant inclusion and exclusion criteria above.  Eligible and enrolled subjects will 
then be reassessed prior to the administration of ibrutinib, which may begin at any point 
between Day +60 and Day +90 after allogeneic HCT, using the pre-ibrutinib inclusion 
and exclusion criteria above.  Ibrutinib will not be initiated until the enrollment checklist 
has been reviewed by the coordinating center; a minimum of 48 hours’ notice is 
required. 
If subjects are deemed ineligible prior to beginning ibrutinib therapy, they may be 
reassessed for eligibility at any point until Day +90 after allogeneic HCT, and ibrutinib 
may be initiated if they meet all relevant criteria at any point between Day +60 and 
Day +90 after allogeneic HCT.  Subjects beyond Day +90 will not be eligible to initiate 
ibrutinib if they have not already done so. 
Pre-transplant screening:  all studies to be completed within 60 days of beginning 
conditioning therapy, unless otherwise indicated: 
• History and physical examination, including Karnofsky Performance Status 
(standard of care) 
• Serologic and/or nucleic-acid testing for HIV, hepatitis B, and hepatitis C 
according to institutional standard practice (standard of care) 
• Serum pregnancy testing, for women of childbearing potential (standard of care) 
• Bone marrow examination, including assessment of minimal residual disease by 
multiparameter flow cytometry or high-throughput sequencing (standard of care) 
• Disease assessment (standard of care):  Data forms for CIBMTR will be made 
available to the coordinating center.  Alternatively, detailed disease assessment 
data will be entered directly into the electronic database. 
• Complete enrollment checklist and submit to coordinating center for review prior 
to enrollment.  Preparative regimen for HCT should not begin until enrollment 
checklist has been reviewed by coordinating center (research). 
Start of preparative regimen through Day +60 to Day +90: 
• Pre-conditioning blood sample from HCT recipient for high-throughput 
sequencing, flow cytometry, and CyTOF (research) 
• Blood sample from HCT donor (related only), as a baseline to investigate 
development of post-transplant GVL effects (research) 
• Disease reassessment between Day +28 and Day +60, including bone marrow 
examination and assessment of minimal residual disease as described above 
(standard of care) 
Prior to administration of ibrutinib (Day +60 to Day +90; all studies should be 
done within 2 weeks of starting ibrutinib): 
• Laboratory assessment of hepatic and renal function (standard of care) 
• Assessment of acute GvHD presence, severity, and therapy history 
(standard of care) 


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• History and physical, including Karnofsky Performance Status 
(standard of care) 
• Assessment of concomitant medications (standard of care) 
• Collection of peripheral blood samples for mixed lymphocyte reactions, Th1/Th2 
assays, and other correlative science endpoints (research) 
Ibrutinib will be initiated between Day +60 and Day +90, after confirmation that the 
subject meets all relevant eligibility criteria.  The drug will be dosed, and doses 
modified, as described below.  The following assessments will be performed after 
initiation of ibrutinib: 
After start of ibrutinib until 2 years post-transplant (tests should be performed 
+/- 2 weeks of given time points through Day +180, and +/- 4 weeks of given timepoints 
after Day +180): 
• History, physical examination, and laboratory assessment of hematologic and 
chemistry tests per institutional standard practice (standard of care) 
• Acute GvHD assessment weekly through Day +100 (standard of care) 
• Chronic GvHD assessment at 6 months, 9 months, 12 months, 15 months, 
18 months, and 2 years post-transplant (standard of care) 
• Toxicity assessment at baseline (before starting ibrutinib), weekly through 
Day +100, monthly until Day +180, and then at 9 months, 12 months, 15 months, 
and 18 months post-transplant (research), unless ibrutinib has been 
permanently discontinued 
• In subjects with AML, myeloid blast crisis, or biphenotypic leukemia:  bone 
marrow examination, including assessment of minimal residual disease by 
multiparameter flow cytometry, at Day +90;  Day +180;  and 1 year 
post-transplant (standard of care).  Please note:  Okay to omit Day +90 MRD 
testing and Day +90 biopsy if previous biopsy (between Day +28 and Day +60) 
showed no evidence of disease.   
• In subjects with ALL or lymphoid blast crisis:  minimal residual disease 
testing by peripheral-blood high-throughput sequencing (ClonoSEQ) at Day +90; 
Day +180; 1 year;  1.5 years;  and 2 years post-transplant (standard of care) 
• Peripheral blood draw for mixed lymphocyte reactions, Th1/Th2 assays, and 
other correlative science at Day +90;  Day +180;  1 year;  1.5 years;  and 2 years 
post-transplant (research) 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
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 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.  


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Medications to be Used with Caution 
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A.  Avoid co-administration with strong 
CYP3A4 or moderate CYP3A inhibitors and consider alternative agents with less 
CYP3A inhibition. 
• If a strong CYP3A inhibitor (eg, ketoconazole;  indinavir;  nelfinavir;  ritonavir;  
saquinavir;  clarithromycin;  telithromycin;  itraconazole;  nefazadone;  or 
cobicistat) must be used, reduce ibrutinib dose to 140 mg or withhold treatment 
for the duration of inhibitor use.  Subjects should be monitored for signs of 
ibrutinib toxicity.  
• If a moderate CYP3A inhibitor (eg, voriconazole;  erythromycin;  amprenavir;  
aprepitant;  atazanavir;  ciprofloxacin;  crizotinib;  darunavir/ritonavir;  diltiazem;  
fluconazole;  fosamprenavir;  imatinib;  verapamil;  amiodarone;  or dronedarone) 
must be used, reduce ibrutinib to 140 mg (for 840 mg/day dose, reduce to 
280 mg) for the duration of the inhibitor use.  Avoid grapefruit and Seville 
oranges during ibrutinib/placebo treatment, as these contain moderate inhibitors 
of CYP3A (see Appendix E Inhibitors and Inducers of CYP3A). 
• No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St John’s Wort).  Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix E.  A 
comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.  This website is continually revised 
and should be checked frequently for updates.  
Drugs That May Have Their Plasma Levels Altered by Ibrutinib 
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. 
QT-prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
ECG and electrolyte monitoring should be considered.  
Antiplatelet Agents and Anticoagulants 
Fatal bleeding events have occurred in subjects treated with ibrutinib.  Grade 3 or 
higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and 
post procedural hemorrhage) have occurred in up to 6% of subjects.  Bleeding events of 


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any grade, including bruising and petechiae, occurred in approximately half of subjects 
treated with ibrutinib.  The mechanism for the bleeding events is not well understood. 
Ibrutinib may increase the risk of hemorrhage in subjects receiving antiplatelet or 
anticoagulant therapies.  See Section 6 (Dose Modification) for recommendations 
regarding ibrutinib dosing in subjects undergoing surgery or other invasive procedures. 
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. 
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 and has no signs of bleeding.  Subjects should be observed closely for signs and 
symptoms of bleeding.  No dose reduction is required when study drug is restarted. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving study treatment with ibrutinib.  Localized, 
hormonal, or bone-sparing treatment for non-hematologic may be considered with 
approval of the PI.  
The Sponsor-investigator must be notified in advance (or as soon as possible 
thereafter) of any instances in which prohibited therapies are administered. 
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 red blood cell growth factors (erythropoietin) is permitted per 
institutional policy and in accordance with relevant institutional and national guidelines.  
Transfusions may be given in accordance with institutional policy. 
Antimicrobial prophylaxis 
All subjects should receive antimicrobial prophylaxis appropriate for allogeneic HCT 
recipients, according to institutional standard practice.  If no institutional standard 
practice exists, one recommended (although not required) approach is as follows: 
• Acyclovir 400 mg TID for 1 year after allogeneic HCT or until discontinuation of 
all systemic immunosuppressive medication, whichever occurs later. 
• Bactrim SS 1 tablet daily for 6 months after allogeneic HCT or until 
discontinuation of all systemic immunosuppression, whichever occurs later. 
• Fluconazole 400 mg daily from start of transplant conditioning until Day +75 after 
allogeneic HCT. 


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Antimicrobial prophylaxis should be adjusted according to subject-specific risks, 
infectious history, institutional susceptibility data, and subjects’ clinical condition. 
4.2 
Criteria for Removal from Study 
Ibrutinib will be continued until 18 months post-transplant, or until one of the following 
occurs:  disease relapse; or discontinuation due to adverse events.  Subjects with 
leukemia relapse after allogeneic HCT will discontinue the study drug, and may be 
treated with any and all appropriate therapies, including investigational agents, at the 
discretion of the treating physician. 
Subjects will be withdrawn from study treatment if one of the following occurs:  leukemia 
relapse; unacceptable toxicity requiring interruption of ibrutinib for more than 28 
continuous days; investigator decision; withdrawal of consent by the subject for further 
treatment and/or follow-up; pregnancy; or study termination.  All enrolled subjects, 
regardless of discontinuation of study treatment, will be followed for leukemia relapse 
and survival until 18 months after allogeneic HCT unless the subject withdraws consent 
for follow-up. 
Withdrawal from the study will occur under the following conditions:  withdrawal of 
consent for follow-up observation by the subject; loss to follow-up; study termination; or 
death.  When an enrolled subject withdraws from the study, the reason for withdrawal 
should be documented, as should the subject’s willingness to participate in follow-up 
visits or assessments. 
4.3 
Alternatives 
The alternative to participation on this study is to receive allogeneic HCT on other 
clinical protocols or treatment plans without the use of maintenance ibrutinib.  This 
alternative will be discussed with subjects during the informed consent process. 
5. 
INVESTIGATIONAL AGENT INFORMATION 
5.1 
 Investigational Agent  
The investigational agent utilized in this clinical trial is ibrutinib, administered at a dose 
of 420 mg orally once-a-day (with dose adjustments for concomitant medications or 
toxicity as described elsewhere in this protocol) and continued for 1 year, until disease 
progression, or until discontinuation due to adverse events.  EXCEPTION:  The starting 
dose for subjects with mild liver impairment (Child-Pugh Class A) is defined to be 
140 mg/day. 
Ibrutinib capsules are size 0, hard gelatin capsules for oral administration and contain 
140 mg of micronized ibrutinib (content may be adjusted for water content and purity) 
and the following compendial excipients (National Formulary, Pharmacopoeia Europe, 
Japan Pharmacopoeia):  microcrystalline cellulose; croscarmellose sodium; sodium 
lauryl sulfate; and magnesium stearate.  Capsules are packaged in high-density 
polyethylene bottles with an induction seal and a child resistant screw-top cap.  The 
number of capsules per bottle is indicated on the label. 


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Ibrutinib capsules should be stored according to the storage conditions indicated on the 
label.  The recommended storage condition for ibrutinib capsules is 15° C to 25° C (59° 
F to 77° F) with excursions permitted to 30° C (86° F).  Ibrutinib should be administered 
orally once daily with a glass of water at approximately the same time each day.  The 
capsules should be swallowed whole with water and should not be opened, broken, or 
chewed.  Ibrutinib must not be taken with grapefruit juice. 
There are limited data on the effects of ibrutinib overdose.  No maximum tolerated dose 
(MTD) was reached in the Phase 1 study in which subjects received up to 
12.5 mg/kg/day (1400 mg).  In a separate study, one healthy subject who received a 
dose of 1680 mg experienced reversible Grade 4 hepatic enzyme increases (AST and 
ALT).  There is no specific antidote for ibrutinib.  Subjects who ingested more than the 
recommended dosage should be closely monitored and given appropriate supportive 
treatment. 
For the most comprehensive information regarding ibrutinib, refer to the current version 
of the Investigator's Brochure. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of Bruton’s tyrosine kinase 
(17).  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 (18). 
Ibrutinib arrested cell growth and induced apoptosis in human B-cell lymphoma cell 
lines in vitro and inhibited tumor growth in vivo in xenograft models (18).  Ibrutinib also 
inhibited adhesion and migration of mantle cell lymphoma (MCL) cells in co-culture and 
reduced tumor burden in lymph node and bone marrow in a murine model of MCL 
dissemination and progression (19). 
Toxicology 
In safety pharmacology assessments, no treatment-related effects were observed in the 
central nervous system or respiratory system in rats at any dose tested.  Further, no 
treatment-related corrected QT interval (QTc) prolongation effect was observed at any 
tested dose in a cardiovascular study using telemetry-monitored dogs.  
Based on data from rat and dog including general toxicity studies up to 13 weeks 
duration, the greatest potential for human toxicity with ibrutinib is predicted to be in 
lymphoid tissues (lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea 
with or without inflammation).  Additional toxicity findings seen in only one species with 
no observed human correlate in clinical studies to date include pancreatic acinar cell 


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atrophy (rat), minimally decreased trabecular and cortical bone (rat) and corneal 
dystrophy (dog).   
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC) in subjects administered the dose of 420 and 560 mg 
daily, respectively.  
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib.  Ibrutinib was not 
mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an 
in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.  Fertility 
studies with ibrutinib have not been conducted in animals.  In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in 
adverse effects on reproductive organs. 
Pharmacokinetics and Metabolism 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day 
as well as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib 
increased as doses increased with substantial intersubject variability.  The mean 
half-life (t1/2) of ibrutinib across 3 clinical studies ranged from 4 to 9 hours, with a median 
time to maximum plasma concentration (Tmax) of 2 hours.  Administration of 420 mg 
ibrutinib with a high-fat breakfast in subjects with CLL approximately doubled the mean 
systemic exposure compared to intake after overnight fasting with median time to Tmax 
delayed from 2 to 4 hours.  Ibrutinib was extensively metabolized to the dihydrodiol 
metabolite PCI-45227, a reversible inhibitor of Btk, with approximately 15-times lower 
inhibitory potency compared to ibrutinib.  The metabolite-to-parent AUC ratio ranged 
from 0.7 to 3.4.  Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold 
of first dose exposure. 
The results of human mass balance study of [14C]-ibrutinib conducted in six healthy 
male subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is 
renally excreted, whereas approximately 80% is recovered in feces.  Subjects with mild 
and moderate renal insufficiency (creatinine clearance > 30 mL/min) were eligible to 
enroll in Study PCYC-1102-CA in which pharmacokinetic (PK) assessments were 
included.  No dose adjustment is needed for mild or moderate renal impairment (greater 
than 30 mL/min creatinine clearance).  There is no data in subjects with severe renal 
impairment or subjects on dialysis.  The study of ibrutinib in hepatic impaired subjects is 
currently in progress. 


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Summary of Clinical Safety  
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 
studies in B-cell malignancies, which includes subjects from 2 randomized-control 
studies who crossed over from comparator treatment or placebo to receive ibrutinib 
monotherapy, are summarized below in Table 1.  
Table 1.  Most frequently reported treatment-emergent adverse events (TEAEs)  
in subjects receiving ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs > 10% 
Most frequently reported 
Grade 3 or 4 TEAEs > 2% 
Most frequently reported 
Serious TEAEs > 1% 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension 
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia 
 
 
For more detailed information refer to the current version of the IB. 
Risks 
Bleeding-related events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both 
with and without thrombocytopenia.  These include primarily minor hemorrhagic events 
such as contusion;  epistaxis;  and petechiae; and some major hemorrhagic events 
including gastrointestinal bleeding;  intracranial hemorrhage;  and hematuria. Use of 
ibrutinib in subjects requiring other anticoagulants or medications that inhibit platelet 
function may increase the risk of bleeding. 
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib.  A 
high number of circulating lymphocytes (> 400,000/µL) may confer increased risk.  
Consider temporarily holding ibrutinib.  Subjects should be closely monitored.  
Administer supportive care including hydration and/or cytoreduction as indicated.  
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% 
increase from baseline and an absolute count > 5000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects with chronic 
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) treated with ibrutinib.  
This effect has also been observed in some subjects with mantle cell lymphoma (MCL) 


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treated with ibrutinib.  This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease in the absence of other clinical findings.  
In both disease types, lymphocytosis typically occurs during the first few weeks of 
ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 
8.0 weeks in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, > 400,000/µL) has been 
observed in some subjects.  Lymphocytosis was not commonly observed in subjects 
with Waldenström’s macroglobulinemia treated with ibrutinib.  Lymphocytosis appeared 
to occur in lower incidence and at lesser magnitude in subjects with CLL/SLL receiving 
ibrutinib in combination with chemoimmunotherapy. 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a 
previous history of atrial fibrillation.  For atrial fibrillation which persists, consider the 
risks and benefits of ibrutinib treatment and follow the protocol dose modification 
guidelines (see Section 6). 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and 
anemia) were reported in subjects treated with ibrutinib.  
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy 
and combination therapy.  Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation.  These events are rarely severe.  Should symptoms 
be severe or prolonged follow the protocol dose modification guidelines (see Section 6).  
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy.  At least 25% of 
subjects with MCL and 35% of subjects with CLL had Grade 3 or greater infections per 
NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0).  The most 
commonly reported infections include pneumonia, cellulitis, urinary tract infection and 
sepsis.  Although causality has not been established, cases of progressive multifocal 
leukoencephalopathy (PML) have occurred in subjects treated with ibrutinib.  Cases of 
hepatitis E, which may be chronic, have occurred in patients treated with ibrutinib. 
Subjects should be monitored for signs and symptoms (such as fever, chills, weakness, 
confusion, vomiting and jaundice, and abnormal liver function tests) and appropriate 
therapy should be instituted as indicated. 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% 
increase from baseline and an absolute count > 5,000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects with CLL/SLL 


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treated with ibrutinib.  This effect has also been observed in some subjects with MCL 
treated with ibrutinib.  This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease in the absence of other clinical findings.  
In both disease types, lymphocytosis typically occurs during the first few weeks of 
ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 
8.0 weeks in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, > 400,000/µL) has been 
observed in some subjects.  Lymphocytosis was not observed in subjects with WM 
treated with ibrutinib.  Lymphocytosis appeared to occur in lower incidence and at lesser 
magnitude in subjects with CLL/SLL receiving ibrutinib in combination with 
chemoimmunotherapy. 
Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib.  Monitor 
subjects for the appearance of non-melanoma skin cancer. 
Rash 
Rash has been commonly reported in subjects treated with either single-agent ibrutinib 
or in combination with chemotherapy.  Rash occurred at a higher rate in the ibrutinib 
arm than in the ofatumumab arm in Study 1112.  Most rashes were mild to moderate in 
severity. 
Tumor lysis syndrome (TLS) 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with 
single-agent ibrutinib or in combination with chemotherapy.  Subjects at risk of tumor 
lysis syndrome are those with comorbidities and/or risk factors such as high tumor 
burden prior to treatment, increased uric acid (hyperuricemia), elevated lactate 
dehydrogenase (LDH), bulky disease at baseline, and pre‐existing kidney abnormalities 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with 
ibrutinib.  Monitor subjects for pulmonary symptoms indicative of ILD.  Should 
symptoms develop, follow the protocol dose modification guidelines (see Section 6). 
5.2 
Availability 
Ibrutinib will be provided for this clinical trial by its manufacturer, Pharmacyclics.  
5.3 
Agent Ordering 
Each study site will order their drug stock through Pharmacyclics.  Ibrutinib will be 
requested from the research pharmacy at each study site. 
5.4 
Agent Accountability 
Ibrutinib will be kept secure according to institutional guidelines and will be processed 
and dispensed by Investigational Drug Services at Stanford University and by 
analogous services at outside collaborating centers.  


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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 experience in the management of ibrutinib overdose in subjects.  
No maximum tolerated dose (MTD) was reached in the Phase 1 study, in which 
subjects received up to 12.5 mg/kg/day (1,400 mg/day).  Healthy subjects were 
exposed up to single dose of 1,680 mg.  One healthy subject experienced reversible 
Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1,680 mg.  Subjects 
who ingest more than the recommended dosage should be closely monitored and given 
appropriate supportive treatment. 
Refer to Section 7.2 for further information regarding AE reporting.  
6. 
DOSE MODIFICATIONS 
The study dose levels of ibrutinib are defined as follows. 
Dose level 0:  420 mg orally once a day. 
Dose level -1:  280 mg orally once a day. 
Dose level -2:  140 mg orally once a day. 
Dose level -3:  Discontinue ibrutinib. 
The dose of ibrutinib should be modified according to the dose modification guidelines 
in Table 2 if any of the following toxicities occur and are considered to be due to 
ibrutinib. 
Hematologic Adverse Events  
• Grade 3 ANC (< 1,000/ µL) with an associated temperature ≥ 38.5°C 
• Grade 4 ANC (< 500/µL) for more than 7 days 
• Grade 3 thrombocytopenia (< 50,000/µL) in the presence of Grade ≥ 2 bleeding 
events 
• Grade 4 thrombocytopenia (< 25,000/µL) 
Non-Hematologic Adverse Events 
• Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy  
• Any other Grade 4 or unmanageable Grade 3 toxicity attributed to ibrutinib 


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Table 2:  Ibrutinib Dose Modifications 
Hematologic Adverse Events  
Occurrence Action to be Taken 
First 
Withhold ibrutinib until recovery to an ANC ≥ 750 or platelets > 25,000 with 
no evidence of Grade ≥ 2 bleeding;  may restart at original dose level 
Second 
Withhold ibrutinib until recovery to an ANC ≥ 750 or platelets > 25,000 with 
no evidence of Grade ≥ 2 bleeding;  may restart at 1 dose level lower  
Third 
Withhold ibrutinib until recovery to an ANC ≥ 750 or platelets > 25,000 with 
no evidence of Grade ≥ 2 bleeding;  may restart at 1 dose level lower  
Fourth 
Discontinue ibrutinib a 
Non-Hematologic Adverse Events 
First 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline;  may restart at original 
dose level 
Second 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline;  may restart at 1 dose 
level lower  
Third 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline;  may restart at 1 dose 
level lower  
Fourth 
Discontinue ibrutinib a 
a  If ibrutinib is discontinued for toxicity, subject will end the Treatment Phase of the 
study. 
Dose changes must be recorded.  At the Investigator’s discretion, the dose of ibrutinib 
may be re-escalated after 8 weeks of a dose reduction in the absence of a recurrence of 
the toxicity that led to the reduction. 
Dose modifications for use with CYP3A inhibitors 
Concomitant use of strong CYP3A inhibitors which would be taken chronically 
(eg, ritonavir;  indinavir nelfinavir;  saquinavir;  boceprevir;  telaprevir;  nefazodone) is 
not recommended.  For short-term use (treatment for 7 days or less) of strong CYP3A 
inhibitors (eg, antifungals and antibiotics) either reduce ibrutinib dose to 140 mg daily or 
withhold ibrutinib therapy until the CYP3A inhibitor is no longer needed.  
Reduce ibrutinib dose to 140 mg orally once daily if a moderate CYP3A inhibitor must 
be used (eg, fluconazole;  darunavir;  erythromycin;  diltiazem;  atazanavir;  aprepitant;  
amprenavir;  fosamprevir;  crizotinib;  imatinib;  verapamil;  and ciprofloxacin).  Subjects 
taking concomitant strong or moderate CYP3A inhibitors should be monitored more 
closely for signs of ibrutinib toxicity. 
As most study subjects are expected to be receiving azoles (fluconazole;  
voriconazole;  posaconazole) until at least Day +75 after allogeneic HCT, the dose 
of ibrutinib will be 140 orally once daily while on such medications.  Once these 
agents are stopped, the dose may be escalated to 420 mg once daily. 


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Dose modifications for hepatic impairment 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant 
hepatic impairment at the time of screening (Child-Pugh Class B or C) are excluded 
from study participation.  For subjects who develop mild liver impairment while on study 
(Child-Pugh Class A), the recommended dose reduction for ibrutinib is to 140 mg daily 
(1 capsule).  Subjects who develop moderate or severe hepatic impairment 
(Child-Pugh Class B or C) will have study drug withheld until resolved to mild 
impairment (Child-Pugh Class A) or better.  Subjects who completely resolve liver 
impairment may re-initiate ibrutinib treatment according to Table 2.  Subjects who 
resolve liver impairment to mild (Child-Pugh Class A) may re-start ibrutinib treatment at 
140 mg daily (1 capsule).  Continue to monitor subjects for signs of toxicity and follow 
dose modification guidance as needed (Refer to Table 2). 
Dose modifications for planned surgery or invasive procedures 
The following recommendations should be considered during the perioperative period 
for subjects who require surgical intervention or an invasive procedure while receiving 
ibrutinib: 
a. For any planned major 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.  
b. 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. 
c. 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. 
Ultimately, the management of ibrutinib in conjunction with invasive procedures 
depends upon the perceived bleeding risk, the subject’s clinical situation, and the 
urgency of the procedure. 
6.1 
Treatment Discontinuation  
Study treatment with ibrutinib will be permanently discontinued for any subject if any of 
the following occur. 
• Grade 4 treatment related (ie, possibly-, probably-, or definitely-related) 
non-hematologic toxicity 
• Grade 4 neutropenia lasting > 21 days  
• Grade 4 thrombocytopenia lasting > 21 days or associated with clinically 
significant bleeding (requiring > 3 units of packed red blood cells within 24 hours 


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to replace loss OR bleeding from a site which in the Investigator’s opinion is a 
potential life-threatening source irrespective of blood loss) 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Please see “Risks” in Section 5.1 above for a full description of known risks and 
toxicities associated with ibrutinib. 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and 
Non-Serious Adverse Events will be clearly noted in source documentation and listed on 
study specific Case Report Forms (CRFs).  The Protocol Director (PD) or designee will 
assess each Adverse Event (AE) to determine whether it is unexpected according to the 
Informed Consent, Protocol Document, or Investigator’s Brochure, and related to the 
investigation.  All Serious Adverse Events (SAEs) will be tracked until resolution, or until 
30 days after the last dose of the study treatment.  
An adverse event (AE) will be defined as any medical change in the subject’s baseline 
or pre-treatment condition (occurring during the course of the clinical study) after 
receiving the study drug (ibrutinib), whether considered treatment-related or not.  
Adverse events will be monitored spontaneously by the subject or will be discovered as 
a result of general questioning by the investigator or by physical examination.  All 
adverse events will be recorded.  As far as possible, each adverse event will be 
described by its duration (start and end dates), frequency (single episode, intermittent, 
continuous), severity (mild, moderate, severe) and assessment of its cause (the 
underlying study indication, co-existing disease, concomitant medication, investigational 
drug, or other), relationship to investigational drug (unrelated, unlikely, possibly, 
probably, definitely), whether it influenced the course of treatment, whether it required 
specific therapy and what is expected or unexpected.  All adverse events will be graded 
on a three point scale of increasing severity.  Serious adverse events will be reported to 
the IRB and appropriate regulatory agencies. 
An adverse event is any significant medical occurrence in a subject treated on this 
protocol both during treatment and follow-up period, regardless of causality 
assessment.  This includes adverse clinical or laboratory findings, inter-current illness, 
or an exacerbation or progression of a condition present at the time of study initiation.  
An adverse event is considered serious if it fulfills one of the following criteria: 
a. Results in death 
b. Life-threatening (subject at risk of death at the time of the event) 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
d. Results in persistent or significant disability 
e. Other medical events that may not be immediately life-threatening or result in 
death or hospitalization by may jeopardize the subject or require intervention to 
prevent one of the outcomes listed above 


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Study subjects will be instructed to report any adverse events to investigators and 
subjects will be evaluated for adverse events at every clinic visit.  All adverse events will 
be documented by investigators and will contain the following information, if known: 
a. Medical diagnosis of the event 
b. Date and time of onset of event 
c. Date and time of resolution of event 
d. Severity of the event according to the National Cancer Institute (NCI) Common 
Toxicity Criteria and Adverse Events (CTCAE) criteria, version 4.0 
e. Frequency of the event 
f. Intervention 
g. Outcome 
h. Likelihood of association between the event and the study drug 
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. 
Serious adverse events (SAEs) CTCAE Grade 3 and above, and all subsequent 
follow-up reports will be reported to the Stanford Cancer Center Data and Safety 
Monitoring Committee (DSMC) using the study specific CRF regardless of the event’s 
relatedness to the investigation.  Following review by the DSMC, events meeting the 
IRB definition of ‘Unanticipated Problem’ will be reported to the IRB using eProtocol 
within 10 working days of DSMC review, or within 5 working days for deaths or 
life-threatening experiences.  If complete information is not available at the time, the 
investigator must provide follow-up information as soon as it is known. 
Adverse events that are serious and unexpected suspected adverse reactions, and are 
possibly, probably, or definitely related to the study drug ibrutinib (SUSAR per 
21CFR§312.32), will be reported to the FDA via IND Safety Report [21CFR§312.32] 


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within 14 calendar days, or within 7 calendar days if the event is an unexpected fatal or 
life-threatening suspected adverse reaction. 
In addition, all serious adverse events (initial and follow-up information) will be reported 
on the Serious Adverse Event Report Form from Pharmacyclics and sent via email or 
fax to Pharmacyclics Drug Safety or designee within 24 hours of the discovery of the 
event or information.  Pharmacyclics may request follow-up and other additional 
information from the Investigator (for instance, hospital admission/discharge notes and 
laboratory results).  The contact information (phone, email and fax) for Pharmacyclics 
Drug Safety can be found on the Serious Adverse Event Report Form and instructions. 
Hematopoietic cell transplantation (HCT) is an aggressive therapy for the treatment of a 
number of life-threatening malignant and non-malignant disorders.  Individuals 
considered for HCT have generally exhausted other avenues of effective therapy.  The 
non-relapse mortality (NRM) associated with a sibling-donor myeloablative allogeneic 
transplant is approximately 20% and the NRM for an unrelated-donor myeloablative 
allogeneic transplant ranges from 20-50%.  In the setting of reduced-intensity 
conditioning and allogeneic HCT, the NRM is approximately 10% with a sibling donor 
and 20% with an unrelated donor. 
As an aggressive therapy, HCT is associated with a large number of AEs and SAEs.  
The toxicities associated with HCT are related to the following:  1) the underlying 
disease;  2) therapy antecedent to HCT;  3) the health status of the transplant recipient, 
including co-existing conditions;  4) the preparative regimen employed before 
transplant;  5) therapies directed at reducing transplant-related complications 
(eg, immunosuppressants for the prevention of GvHD);  and 6) the treatment of 
complications of HCT.  
The use of toxicity grading scales such as the NCI CTC is a standard in the medical 
community for the reporting of AEs and SAEs in the investigation of new drugs or 
devices.  The use of this type of scale is less helpful in the evaluation of AEs and SAEs 
associated with a treatment, such as HCT.  In an effort to report to regulatory agencies 
the toxicities that are relevant and meaningful for the evaluation of risks and benefits to 
potential HCT recipients, the following guidelines will serve to determine which events 
are reported as AEs and SAEs. 
The following SAEs require reporting to the Stanford Cancer Institute Data Safety 
Monitoring Board for subjects on research protocols.  If the event is unexpected, 
serious, and harmful, then it will also require reporting to the IRB: 
1) Deaths  
All deaths: 
• while the subject is receiving treatment on a protocol  
• up to 60 days (autologous) or 90 days (allogeneic) after last dose of protocol 
treatment 
• or any death that occurs more than 60 days (autologous) or 90 days (allogeneic) 
after protocol treatment has ended that is felt to be treatment related. 


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Reports will include deaths from the common and expected Grade 4 toxicities noted 
below.  Deaths that occur outside of Stanford will be reported whenever possible.  It 
must be noted that obtaining detailed information on the cause and circumstances of a 
death occurring at another institution can be difficult.  Excludes deaths related to 
relapse of underlying disease, which will reported to the IRB at the time of protocol 
renewal.  
2) All serious and unexpected toxicities 
Defined as those toxicities not identified in the transplant literature, product inserts, or 
study consent form. 
The following will be recorded, but generally will not be reported as AEs or SAEs, 
unless also considered related to the study drug.   
1) Hospitalizations  
Approximately 50% of allogeneic transplant recipients will be readmitted to the 
hospital.  The most common indications for readmission of an allogeneic HCT 
recipient are fever, failure to maintain nutritional status, and GvHD.  NOTE:  Events 
that result in hospitalization or extend hospitalization will still be considered SAEs.  
2) Relapse of disease 
Relapse unfortunately remains a significant problem following both autologous and 
allogeneic HCT.  The risk of relapse is influenced by both subject and disease 
variables.  The risk of relapse following allogeneic transplant is extremely dependent 
on the disease being treated but ranges from 10% (for subjects with severe aplastic 
anemia) to 80% (for subjects with refractory acute leukemia). 
3) Common and expected toxicities of HCT ≤ Grade 4 that are well-described in 
transplant literature, the product inserts, or study consent form and do not 
result in death. 
In general, these toxicities are considered reversible.  The specific reporting 
requirements are found in the protocol.  These Grade 4 toxicities include, but are not 
limited to, alopecia, anemia, anorexia, bleeding requiring transfusions, cardiac 
arrhythmias , central venous catheter infections, constipation, diarrhea, edema, 
fatigue, febrile episodes, gastritis, graft failure, graft versus host disease, hematuria , 
hypertension, hypotension, hypoxia, incontinence, infections, insomnia, laboratory 
abnormalities, mental status changes, mood alterations, mucositis, nausea , 
neutropenia, pain, pleural effusion, pneumonitis, rash, seizures, sepsis, sinusoidal 
obstructive syndrome, tachycardia, thrombocytopenia, thrombotic microangiopathy, 
tremor, vomiting.  For IND studies, SAEs that are SUSARs per 21CFR§312.32 will 
be reported as IND Safety Reports (see above).  
4) Acute and chronic GvHD 
Acute and chronic GvHD are major complications of HCT and account for most 
non-relapse mortality.  The incidence of GvHD will be reported as part of the 
secondary outcomes and to the IRB at the time of the protocol annual review. 


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5) Secondary Malignancies 
The occurrence of secondary malignancies and associated mortality is a known risk 
of cancer therapies.  The occurrence of secondary malignancies will be reported to 
the IRB at the time of the protocol annual review. 
6) Special reporting situations which may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• Overdose of any study drug 
• Suspected abuse/misuse of a study drug 
• Inadvertent or accidental exposure to a study drug 
• Medication error involving a product (with or without subject exposure to the 
study drug) 
Occurrence of any special reporting situation should be recorded in the CRF.  If any 
special reporting situation meets the criteria for an adverse event, it should be 
recorded on the adverse events CRF.  If the adverse event is considered serious, it 
should be recorded on the adverse events CRF 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 Pharmacyclics Drug Safety or designee within 15 days of 
awareness. 
Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of 
standard safety monitoring activities.  The following events (regardless of seriousness) 
will be reported to Pharmacyclics Drug Safety per SAE reporting timelines.  
Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
• Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*.  Any 
treatment-emergent serious adverse events of bleeding of any grade 
• Any treatment-emergent central nervous system hemorrhage/hematoma of any 
grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported 
as Grade 3 or higher AE per CTCAE v4.0. 
Events meeting the definition of major hemorrhage will be captured as an event of 
special interest. 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events and AESIs (initial and follow-up information) will be 
reported on FDA Medwatch (Form 3500A) or Suspect Adverse Event Report 
(CIOMS Form 1) IRB Reporting Form and sent via email (
@pcyc.com) 
or fax (408-215-3500) to Pharmacyclics Drug Safety, or designee, within 15 days of 


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the event.  Pharmacyclics may request follow-up and other additional information 
from the Sponsor Investigator.  
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) 
8. 
CORRELATIVE/SPECIAL STUDIES  
We propose a series of correlative laboratory studies using blood samples collected 
from study participants, with the aim of elucidating the impact of ibrutinib on immune 
reconstitution after allogeneic HCT and on the development of alloreactivity, 
graft--vs-tumor effects, and GvHD. 
Background 
Alloreactive T- and B-cells play a crucial role in development of both beneficial 
graft-vs-tumor effects and harmful GvHD after allogeneic HCT.  In chronic GvHD, 
T follicular helper cells (TFH), Th2, and Th17 T-cells activate B-cells and elicit fibrotic 
cascades underpinned by alloantibody production and collagen deposition.  To 
understand the impact of ibrutinib on alloreactivity after allogeneic HCT, we will perform 
global B- and T-cell immune phenotype analysis using multiplexed CyTOF analysis, 
focused on quantifying Th2 subversion and cytotoxic T-cell preservation, T follicular cell 
composition, and T-cell functional activation.  These laboratory assays will be correlated 
with clinical evidence of GvHD and GVL effects (quantified by measuring minimal 
residual disease via sequencing of T- and B-cell immune receptors with clonoSEQ 
technology (in subjects with ALL) and via multi-parameter flow cytometry (in subjects 
with AML).  
T- and B-cell repertoire reconstitution will be monitored via immune receptor 
high-throughput sequencing (HTS) and H-Y alloreactive B-cell phenotyping.  We will 
determine the effect of ibrutinib on serum immunoglobulin levels, cytokine quantification, 
protective anti-EBV and anti-tetanus immunity, and allogeneic H-Y antibody responses 
after allogeneic HCT. 
Minor histocompatibility antigens expressed on the Y chromosome are called H-Y 
antigens and are frequently targeted by female donor lymphocytes when male subjects 
undergo sex-mismatched transplantation (FM HCT).  Dr Miklos’ lab has demonstrated 
that H-Y specific B-cells and antibodies are associated with chronic GvHD following 
FM HCT.  We hypothesize that ibrutinib will preferentially target and deplete 


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alloreactive B-cell.  While H-Y antigen provides a model system to study 
antigen-specific alloimmunity, H-Y can only be studied in male subjects with female 
donors (FM HCT).  Recognizing this limitation for H-Y antigen studies, as well as 
limitations in the number of PBMC available for research per subject, we have decided 
to dedicate FM HCT subject samples to H-Y B-cell analyses while using samples from 
all other donor and recipient sex combinations (not FM) for T-helper cell and 
functional T-cell analyses as shown in Table 3 below.  Historically, FM allotransplants 
account for 35-40% of cases of chronic GvHD. 
Sample collection 
As in the PCYC 1129 protocol, 50 mL of blood will be collected in five 10 mL 
heparinized green-top tubes before the start of conditioning therapy; before ibrutinib 
intiation; and then again at Day +180, 1 year, and 1.5 years after allogeneic HCT.  We 
will also obtain blood samples from the HCT donor.  The 50 mL aliquots of recipient 
blood will be processed on-site at Stanford University, providing three vials of 1.5 mL 
plasma and five 1 mL vials of viably frozen peripheral blood mononuclear cells (PBMC) 
separated by Ficoll gradient centrifugation as described in the PCYC1129 laboratory 
manual.  PBMC cell yields will be recorded and evenly distributed into five vials 
irrespective of cell quantity.  Plasma will be stored at -80° C and PBMC will be stored in 
liquid nitrogen on-site.  Comprehensive multiplexed B- and T-cell phenotype analysis 
will be performed on all samples at all time points using CyTOF.  In addition, B- and 
T-cell repertoire analyses will be determined using immune receptor high-throughput 
sequencing (HTS).  We plan to reserve a single vial of PBMC and 1 mL plasma per 
subject in central storage, in case trial investigators identify additional informative 
studies later. 
Table 3.  Schedule of correlative laboratory studies. 
 
 
Pre- 
HCT 
Pre- 
Ibrut. 
6 m 
12 m 
18 m 
CyTOF B- and T-cell phenotyping (PBMC 1) 
Res. 
All 
All 
All 
All 
All 
T-cell repertoire analysis by immune receptor 
sequencing (PBMC 2) 
Res. 
All 
All 
All 
All 
All 
B-cell repertoire analysis by immune receptor 
sequencing (PBMC 2) 
ALL SOC 
AML Res 
 
 
 
 
All 
IgG & IgM quantification 
SOC 
All 
All 
All 
All 
All 
Cytokine Analysis and BAFF (plasma 1) 
Res. 
All 
--- 
--- 
All 
All 
T-Follicular quantification (PBMC 3) 
Res. 
All but 
FM 
All but 
FM 
All but 
FM 
All but 
FM 
All but 
FM 
H-Y alloreactive Antibodies (Plasma 2) 
Res. 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
H-Y specific B-cell characterization (PBMC 4) 
Res. 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
Abbreviations:  HCT, hematopoietic cell transplantation;  Ibrut, ibrutinib;  m, months;  Res, research;  
SOC, standard of care;  AML, acute myeloid leukemia;  ALL, acute lymphoblastic leukemia;  
F->M, female-donor-to-male-recipient;  PBMC, peripheral blood mononuclear cells 


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Preliminary data
We performed immune phenotyping on peripheral blood samples collected from 
12 subjects who underwent allogeneic HCT for chronic lymphocytic leukemia and who 
were treated with ibrutinib for post-transplant relapse.  In these subjects, ibrutinib rapidly 
depleted pre-germinal-center B-cells (CD19+CD38+CD27+IgD+), which have previously 
been associated with development of chronic GvHD.  In contrast, memory B-cells 
(CD19+CD27+IgD-CD38-) persisted, and total serum IgG levels were maintained despite 
ibrutinib treatment.  Subset analysis of T-cells showed a 75% reduction in 
GATA3-expressing Th2 cells, while Tbet-expressing Th1 cells remained unaffected.  
T follicular cells (CD4+CXCR5+BCL6+) were likewise depleted rapidly from the 
circulation by ibrutinib treatment (Figure 1).  Taken together, these preliminary results 
support the hypothesis that ibrutinib treatment after allogeneic HCT will result in Th1 
polarization of the T-cell repertoire, preservation of CD8+ T-cells, and depletion of T 
follicular cells, all of which would be expected to reduce GvHD risk while maintaining 
beneficial anti-tumor alloreactivity.  Of note, these preliminary data were obtained in 
subjects treated with ibrutinib for relapse, while the proposed study herein attempts to 
elucidate the role of maintenance ibrutinib on immune reconstitution and GvHD.
Figure 1.  Changes in peripheral B-cell and T-cell subsets after treatment with ibrutinib 
in subjects with relapsed CLL after allogeneic HCT
Correlative science aims
1. Perform immunophenotyping of peripheral-blood B- and T-cells before and after 
initiation of maintenance ibrutinib.
a. Evaluate Th1 polarization, effect on T follicular cells, and CD8+ cytotoxic T 
lymphocytes
b. Evaluate B-cell reconstitution by quantifying transitional, naïve, memory, and 
activated plasmablast fractions
CD19+ B Cells
CD3+ T Cells


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c.  Determine concentrations of Th1 and Th2 cytokines in plasma 
2. Characterize the B- and T-cell repertoire during and after ibrutinib maintenance 
using immune receptor high-throughput sequencing to assess clonal expansion of 
donor cytotoxic T-cells and follicular T-cells. 
a.  Compare to results from patients transplanted at our institution without 
maintenance ibrutinib 
b.  Quantify EBV-specific T-cell reconstitution 
3. Assess B-cell function before and after initiation of maintenance ibrutinib 
a.  Evaluate for presence of alloreactive B-cells and H-Y antibodies in F->M 
allogeneic HCT 
b.  Quantify total serum immunoglobulin levels 
c.  Quantify protective anti-EBV and anti-tetanus antibodies 
d.  Assess levels of BAFF before, during, and after ibrutinib maintenance treatment 
These laboratory studies will be correlated with clinical data (including onset, severity, 
and response of chronic GvHD and minimal residual disease detection of leukemia). 


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9. 
STUDY CALENDAR 
Studies shown in italics are research studies, while evaluations shown in black 
represent clinical standard of care. 
 
Within 
60 days of 
starting 
conditioning 
Between 
Day +28 
and 
Day +60 
Start of 
ibrutinib 
(between 
Day +60 
and 
Day +90) 
Day 
+90 
Day 
+180 
9 
months 1 year 
15 
months  
18 
months 
2 
years 
Off 
Study 
Eligibility determination 
X 
X 
 
 
 
 
 
 
 
 
 
History & physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KPS assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory testing of 
hepatic and renal function 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transplant evaluation per 
institutional criteria 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG)  
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for women 
of childbearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration 
and/or biopsy with 
assessment of minimal 
residual disease  
X 
X 
 
AML 
only* 
AML 
only 
 
AML 
only 
 
 
 
 
Minimal residual disease 
detection by 
peripheral-blood 
high-throughput 
sequencing (ClonoSEQ) 
X 
X 
 
X* 
X 
 
X 
 
X 
X 
 
Assessment of 
concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Acute GvHD assessment 
 
X 
 
X 
 
 
 
 
 
 
 
Chronic GvHD assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Ibrutinib (study drug) 
 
 
 
X ------------------------------------------------------X 
Adverse event evaluation 
 
 
 
X-------------------------------------------------------X 
Blood draw for biological 
studies 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Blood sample from HCT 
donor (related only) 
X 
 
 
 
 
 
 
 
 
 
 
For the Day +90 and Day +180 timepoints, the relevant evaluations may be performed within +/- 2 weeks 
of the specified timepoint.  For the 9-month, 1-year, 15-month, and 18-month timepoints, the relevant 
evaluations should be performed within +/- 4 weeks of the specified timepoint.   
* Please note:  Okay to omit Day +90 MRD testing and Day +90 biopsy if previous biopsy (between 
Day +28 and Day +60) showed no evidence of disease.   


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10. 
MEASUREMENTS 
10.1  Primary and Secondary Outcome measures 
The primary outcome measure is the incidence of relapsed leukemia at 18 months after 
allogeneic HCT.  This is an efficacy endpoint. 
Secondary endpoints include the incidence of acute GvHD Grades II–IV and III–IV at 
Day +180 after allogeneic HCT, the incidence of chronic GvHD at 18 months after 
allogeneic HCT, and the incidence of detectable minimal residual disease at 1 year after 
allogeneic HCT. 
10.1.1 Relevant Subsets 
The primary and secondary outcomes will be measured on all enrolled subjects. 
10.1.2 Measurement Definition 
For the primary outcome measure, relapsed leukemia is defined as > 5% leukemic 
blasts detected in bone marrow or peripheral blood.  Subjects will also be considered to 
have relapsed leukemia if they receive any active treatment for progressive leukemia 
after allogeneic HCT, even if they have <5% leukemic blasts.  Withdrawal of 
immunosuppression alone is not considered an active treatment for progressive 
disease. 
For the secondary outcome measures, acute GvHD will be graded and scored 
according to standard criteria (Appendix C).  Chronic GvHD will be graded and scored 
according to the 2014 NIH consensus criteria (Appendix D).  Minimal residual disease 
will be assessed by high-throughput sequencing (ClonoSEQ) for subjects with ALL, and 
by high-sensitivity flow cytometry for subjects with AML or acute biphenotypic leukemia.  
Minimal residual disease will be considered present if > 1 x 10-6 leukemic clones are 
detected by ClonoSEQ (20), or if any aberrant blasts matching the original leukemic 
immunophenotype are detected by high-sensitivity flow cytometry (21). 
10.1.3 Measurement Methods and Time Points 
The primary outcome will be measured by bone marrow examination at Day +90;  
Day +180;  and 1 year after allogeneic HCT in subjects with AML or myeloid leukemias, 
and by peripheral-blood high-throughput sequencing on Day +90;  Day +180;  1 year;  
18 months;  and 2 years post-transplant in subjects with ALL.  Minimal residual disease 
detection by high-throughput sequencing is not itself diagnostic of relapse, but should 
prompt a bone marrow examination to assess definitively for relapse.  Routine 
monitoring of peripheral blood counts and differential will also be performed according 
to clinical standards of care, with bone marrow examination performed in response to 
any concerning findings to assess for relapse. 
The secondary outcomes will be measured as follows:  acute GvHD will be scored 
weekly (if returning to the transplant center that frequently) from initiation of ibrutinib 
through Day +100 using the criteria described above.  Chronic GvHD will be assessed 
at Day +180, at 9 months, at 1 year, at 15 months, and at 18 months after allogeneic 


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HCT, using the criteria described above. Minimal residual disease will be assessed as 
described above on Day +90;  Day +180;  1 year;  and 18 months after allogeneic HCT. 
For the Day +100 and Day +180 timepoints, the relevant evaluations may be performed 
within +/- 2 weeks of the specified timepoint.  For the 9-month; 1-year; 15-month;  and 
18-month timepoints, the relevant evaluations should be performed within +/- 4 weeks of 
the specified timepoint. 
11. 
REGULATORY CONSIDERATIONS 
11.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (eg, advertisements used to recruit participants) will be reviewed 
and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review 
Committee (SRC).  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  The Protocol 
Director will disseminate the protocol amendment information to all participating 
investigators. 
11.2 Data and Safety Monitoring Plan 
Primary internal data monitoring will be performed by the Overall Protocol Director at 
Stanford and site investigators and their research staff.  The Protocol Director will 
review data to assure the validity of data, as well as the safety of the subjects.  The 
Protocol Director will also monitor the progress of the trial.  The Protocol Director will be 
responsible for maintaining the clinical protocol, reporting adverse event, assuring the 
consent is obtained and documented, reporting of unexpected outcomes and reporting 
the status of the trial in the continuing renewal report submitted annually to the IRB and 
SRC. 
A safety monitoring committee (SMC) will be composed of the Protocol Director and 
research staff, including other site principal investigators.  The SMC will conduct regular 
teleconferences on at least a quarterly basis or more frequent communication between 
the Protocol Director and research staff may occur via email or teleconference as 
necessary. 
The data will be monitored continuously over the accrual and follow up periods by the 
investigators and the study coordinators.  The Protocol Director will be responsible for 
maintaining the clinical protocol, reporting adverse event, assuring the consent is 
obtained and documented, reporting of unexpected outcomes and reporting the status 
of the trial to the IRB and the Stanford University Cancer Center Data Safety Monitoring 
Board (DSMB). 
11.3 Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  
Study-specific electronic Case Report Forms (eCRFs) will document treatment 
outcomes for data analysis.  The RedCAP database system will be used and 
maintained by the PI and/or his designees.  The eCRFs will be secured via confidential 
username and password access to the research team. 


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11.4 Confidentiality 
Subjects may be referred to this clinical trial from outside of Stanford.  Therefore, study 
subjects will be assigned a unique study identification (ID) number.  Referring 
physicians will be sent letters by the BMT physicians updating them on their subject's 
status, including information regarding the expected side effects of the treatment, 
necessary precautions and also the appropriate follow-up.  Specific information 
regarding the study would not be routinely shared with the referring physician. 
Subjects will be assigned a study-specific identification number (a unique number) and 
their data are entered into a secure database.  Access to the database is 
password-restricted and limited to study personnel.  
Research records will be maintained in a secure BMT office, and electronic data will be 
maintained in a study-specific, secure database.  In addition, information from the main 
Stanford BMT database may be uploaded into the study-specific database.  
All study staff will be required to complete HIPAA training.  All research staff must 
complete the IRB human subjects research training.  The study subject data are 
identified by a unique study ID number in the research documents.  Access to the 
research database is limited to approved clinical and research staff.  The code is 
maintained by the Stanford’s BMT Database System Administrator, and kept in a secure 
location.  
Study subjects will not be directly identified in any publications, presentations or 
correspondence. 
Private Health Information (PHI) is collected and recorded at the time of the subject’s 
first consultation with the BMT program.  Additional information is collected when the 
subject is enrolled in a clinical trial.  PHI may include some or all of the following: 
1. Names and initials 
2. Telephone numbers  
3. Addresses including ZIP code 
4. Dates, including date of birth 
5. Age;  sex;  race;  and ethnicity 
6. Email addresses  
7. Identification numbers, including Medical record numbers (MRNs) and Stanford 
Patient Number (SPN) 
8. Relevant medical history as it pertains to their BMT history, malignancy for which 
they received their BMT, acute and chronic GvHD history, past treatments for 
GvHD, vital signs, diagnostic test results, laboratory values, physical exam 
findings, past medical history, including relevant family medical history 
(eg, coronary heart disease, diabetes, hypertension, etc) that may place them at 
risk for side effects, medication history/current medications, interval history since 
last clinic visit, current health complaints, GvHD assessment, and treatment plan. 
Other outside agencies that may receive information include:  
• 
Pharmacyclics LLC, its affiliates or collaborators (eg, Janssen Biotech, Inc.) or 
their representatives  


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• 
The Office for Human Research Protections (OHRP) in the US Department of 
Health and Human Services (DHHS)  
• 
The Food and Drug Administration 
• 
The US Centers for Medicare & Medicaid Services (CMS), the agency 
responsible for administration of the Medicare program  
• 
Other federal and/or regulatory agencies as required 
• 
Center for International Blood and Marrow Transplant Research (CIBMTR)  
• 
The National Institutes of Health (NIH) / National Cancer Institute (NCI) / National 
Heart, Lung, and Blood Institute (NHLBI) 
• 
Stanford Data Safety Monitoring Board 
• 
Other Stanford investigators with IRB-approved projects (researchers outside of 
the BMT program will not have access to subject’s identity or personal protected 
health information (PHI).  The data will be managed using a database program.  
Data sets may be generated to share with investigators outside the program by 
de-identifying the data). 
Samples will be identified by the Subject ID number.  Research records are kept in a 
locked office.  Access to the office is limited to key access.  Only study personnel within 
the research program have access to the electronic database, the research records, or 
the code linking the samples to subject’s identifying information.  
11.5 Reporting Mechanisms 
The study Protocol Director (or designee) will be responsible for the coordination and 
development of all protocol amendments.  Any changes to the protocol or consent will 
be made in the form of an eProtocol modification, and will be approved prior to 
implementation.  Any amendments to the Protocol or Informed Consent Form protocol 
must be sent to Pharmacyclics for review and approval prior to submission to the IRB.  
This process will be included in the monitoring plan.  Changes or amendments to the 
protocol or consent will be reported to the IRB, FDA and NHLBI.  All IRB actions will be 
reported to the DSMC, NHLBI and FDA.  
12. 
STATISTICAL CONSIDERATIONS 
12.1 Statistical Design, Effect Size, and Sample Size 
This study is designed as a single-arm efficacy trial using historical published controls.  
This study’s primary endpoint is the incidence of relapse at 18 months after allogeneic 
HCT for AML/ALL.  Baseline relapse rates after reduced-intensity conditioning for these 
diseases in the published literature vary from 40–60% (1-6).  For the purposes of study 
design, we will use a relatively conservative baseline relapse risk of 45%.  This study is 
designed to detect a decrease in relapse rate from 45% to 25%.  Therefore, in the 
power analysis we will assume that the true relapse rate in the study population is 25%, 
while the null hypothesis holds that the relapse rate is 45%.  Under these conditions, 
using intent-to-treat analysis, a sample size of 50 enrolled subjects will provide 84% 
power to conclude that the relapse rate is lower than 45% at the two-sided significance 
level of 0.05.  Conservatively assuming that 45 of these 50 subjects meet the secondary 
criteria to continue to ibrutinib treatment (Appendix B) and are treated with ibrutinib, a 
subgroup analysis restricted to these 45 subjects will have 78% power to conclude that 
the relapse rate is < 45% with a significance level of 0.05. 


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12.2 Interim analyses 
We will monitor major adverse event rates as described above, in particular serious 
bleeding complications (hemorrhage Grade 3 or 4, as defined by CTCAE v4.0).  We will 
monitor and estimate the incidence rate of serious bleeding in study participants, and 
report all occurrences and corresponding analytic summaries (such as the estimated 
incidence rate with 95% confidence intervals) to the DSMB to assist in decision-making 
regarding early termination for safety. 
Allogeneic HCT is an intensive therapy with many associated side effects and toxicities 
related to the transplant conditioning regimen;  the ensuing immunosuppressed status;  
adverse effects of standard post-transplant medications;  and graft-vs-host interactions 
or GvHD.  Toxicities, including Grade 4 toxicities, are relatively common.  Non-relapse 
mortality (NRM) is a definitive endpoint which captures fatal effects of any aspect of the 
transplant process outside of disease relapse, and thus represents the most accurate 
and reproducible measure of the toxicity and safety of the allogeneic HCT process.  
The baseline cumulative incidence of NRM after allogeneic HCT for acute leukemia with 
FLU/MEL conditioning was estimated in a recent large cohort study at 20% (22).  
In order to ensure that patients are not harmed by the study intervention, the formal 
stopping rule below monitors that the study intervention does not increase the risk of 
NRM in participants.  
The stopping rule is based on the incidence of NRM at 1 year after allogeneic HCT.  
Patients will be evaluable with regard to the stopping rule if they die or if they reach 
1 year post-transplant, whichever occurs first.  The stopping rule will be tested every 
increment of 5 evaluable patients.  The stopping rule will be triggered if any of the 
following conditions are met:  
Number of 
evaluable patients 
Number of patients 
with NRM 
5 
3 
10 
5 
15 
6 
20 
8 
25 
9 
30 
10 
35 
12 
40 
13 
If the stopping rule is triggered, the study will be terminated, and FDA so notified.  This 
stopping rule provides 80% power to detect an increase in NRM with a type I error rate 
of 0.05.  The stopping rule was constructed using the Pocock boundary with the same 
significance level for all looks at the data.  The rule was created using R v.3.1.3 and the 
clinfun package.  


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12.3 Analysis Population 
Subjects who are enrolled but never treated with ibrutinib (eg, due to failure to meet the 
secondary criteria to continue to ibrutinib treatment) will be included in the primary 
analysis, which will be performed as an intention-to-treat analysis.  However, they will 
not be counted toward the overall accrual goal of 45 subjects.  A planned subset 
analysis will be performed testing the primary and secondary endpoints in the subset of 
subjects who receive at least 1 dose of ibrutinib on study. 
12.4  
Accrual estimates  
 
We performed 36 reduced-intensity allogeneic HCT for AML/ALL at Stanford in calendar 
year 2014.  We will also plan to open this study at UCSF (with Dr Aaron Logan) and City 
of Hope (with Dr Alex Herrera).  We anticipate accruing 10 to 15 subjects annually at 
UCSF and 20 subjects annually at City of Hope, based on their historical transplant 
patterns.  We therefore expect that study accrual will take 1 year to complete. 


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13. REFERENCES 
1. 
Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, et al. Comparative 
outcome of reduced intensity and myeloablative conditioning regimen in HLA identical 
sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years 
of age with acute myeloblastic leukaemia:  a retrospective survey from the Acute Leukemia 
Working Party (ALWP) of the European group for Blood and Marrow Transplantation 
(EBMT). Leukemia. 2005;19(12):2304-12. 
2. 
Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R, et al. Impact of conditioning 
regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced 
acute myelogenous leukemia and myelodysplastic syndrome. Biology of blood and marrow 
transplantation :  journal of the American Society for Blood and Marrow Transplantation. 
2006;12(10):1047-55. 
3. 
Shimoni A, Hardan I, Shem-Tov N, Yerushalmi R, Nagler A. Allogeneic hematopoietic 
stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity 
conditioning:  long-term follow-up. Leukemia. 2010;24(5):1050-2. 
4. 
Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R, et al. Comparison 
between two fludarabine-based reduced-intensity conditioning regimens before allogeneic 
hematopoietic stem-cell transplantation:  fludarabine/melphalan is associated with higher 
incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence 
of relapse than fludarabine/busulfan. Leukemia. 2007;21(10):2109-16. 
5. 
Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ, et al. Comparative outcome of 
nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for 
patients older than 50 years of age. Blood. 2005;105(4):1810-4. 
6. 
Mohty M, Labopin M, Volin L, Gratwohl A, Socie G, Esteve J, et al. Reduced-intensity 
versus conventional myeloablative conditioning allogeneic stem cell transplantation for 
patients with acute lymphoblastic leukemia:  a retrospective study from the European 
Group for Blood and Marrow Transplantation. Blood. 2010;116(22):4439-43. 
7. 
Bishop GA, Haxhinasto SA, Stunz LL, Hostager BS. Antigen-specific B-lymphocyte 
activation. Crit Rev Immunol. 2003;23(3):149-97. 
8. 
Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies:  the dark side of B-cell 
differentiation. Nat Rev Immunol. 2002;2(12):920-32. 
9. 
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and 
function:  a genetic perspective. Immunological reviews. 2000;175:120-7. 
10. Rushworth SA, Murray MY, Zaitseva L, Bowles KM, MacEwan DJ. Identification of Bruton's 
tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood. 
2014;123(8):1229-38. 
11. Zaitseva L, Murray MY, Shafat MS, Lawes MJ, MacEwan DJ, Bowles KM, et al. Ibrutinib 
inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget. 2014;5(20):9930-8. 
12. ClinicalTrials.gov. NCT02129062:  Ibrutinib in Treating Patients With Relapsed or 
Refractory B-cell Acute Lymphoblastic Leukemia:  National Institutes of Health;  [Available 
from:  https://clinicaltrials.gov/ct2/show/NCT02129062. 
13. Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, et al. 
Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. 
Blood. 2009;113(16):3865-74. 
14. Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, et al. Ibrutinib 
treatment ameliorates murine chronic graft-versus-host disease. The Journal of clinical 


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investigation. 2014;124(11):4867-76. 
15. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib 
is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T 
lymphocytes. Blood. 2013;122(15):2539-49. 
16. Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, et al. Tacrolimus/sirolimus 
vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic 
HCT. Blood. 2014;124(8):1372-7. 
17. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, et al. Discovery of 
selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 
2007;2(1):58-61. 
18. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton 
tyrosine kinase represents a promising therapeutic target for treatment of chronic 
lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011;117(23):6287-96. 
19. Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, et al. 
Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton 
tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 
2013;122(14):2412-24. 
20. Logan AC, Vashi N, Faham M, Carlton V, Kong K, Buno I, et al. Immunoglobulin and T cell 
receptor gene high-throughput sequencing quantifies minimal residual disease in acute 
lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biology of 
blood and marrow transplantation:  journal of the American Society for Blood and Marrow 
Transplantation. 2014;20(9):1307-13. 
21. Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, et al. Comparison 
of minimal residual disease as outcome predictor for AML patients in first complete 
remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell 
transplantation. Leukemia. 2014. 
22. Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz MA, et al. Reduced-intensity 
conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients 
with acute myeloid leukemia:  a report from the Acute Leukemia Working Party of the 
European Group for Blood and Marrow Transplantation. Cancer. 2015;121(7):1048-55. 
23. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic 
Graft-versus-Host Disease:  I. The 2014 Diagnosis and Staging Working Group report. 
Biology of blood and marrow transplantation:  Journal of the American Society for Blood 
and Marrow Transplantation. 2015;21(3):389-401 e1. 
 


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APPENDICES 
APPENDIX A:  Pre-Transplant Eligibility Checklist  
Protocol Title: 
A Phase 2 Study of Ibrutinib After Reduced-Intensity 
Conditioning and Allogeneic Hematopoietic Cell 
Transplantation for Acute Leukemia 
Protocol Number: 
IRB-38934  /  BMT302 
Principal Investigator: 
Andrew R Rezvani, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC-Approved 
 IRB-Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria 
Pre-transplant screening:  all studies to be completed within 60 days of beginning 
conditioning therapy, unless otherwise indicated: 
 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Diagnosis of acute myeloid leukemia (AML), 
acute biphenotypic leukemia, or acute 
lymphoblastic leukemia (ALL).  (CML 
transformed to blast crisis is eligible). 
 
 
      
2. Planned allogeneic HCT using FLU/MEL or 
FLU/BU conditioning (as defined in protocol). 
 
 
      
3. Planned GvHD prophylaxis with TAC/MTX or 
TAC/SRL (regimens defined in protocol). 
 
 
      
4. HLA-identical sibling donor, HLA-matched 
unrelated donor, or donor mismatched at 1 HLA 
allele or antigen. 
 
 
      
5. Less than or equal to 5% blasts on bone marrow 
examination within 60 days of starting 
conditioning. 
 
 
      
6. Age ≥ 18 years and ≤ 70 years. 
 
 
      
7. Able to give informed consent. 
 
 
      
 


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Exclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Active involvement of the central nervous system 
with malignancy (previous CNS involvement is 
allowed if clearance of CNS disease has been 
documented prior to enrollment) 
 
 
      
2. Pregnant or breastfeeding 
 
 
      
3. Karnofsky Performance Status <60% 
 
 
      
4. Active leukemia (> 5% leukemic blasts in 
peripheral blood or bone marrow) 
 
 
      
5. Non-hematologic malignancy with life expectancy 
< 5 years 
 
 
      
6. HIV positivity, active hepatitis C virus infection, or 
active hepatitis B virus infection.  (Subjects positive 
for HBV surface antigen or HBV core antibody are 
eligible if they have a negative HBV PCR before 
enrollment.  Those who are PCR-positive are not 
eligible) 
 
 
      
7. Known bleeding disorder (eg, von Willebrand’s 
disease, hemophilia) 
 
 
      
8. History of other malignancies, except: 
o Malignancy treated with curative intent and with 
no known active disease for at least 3 years 
before the first dose of study drug, and felt to be 
at low risk of recurrence by treating physician 
o Adequately treated non-melanomatous skin 
cancer or lentigo maligna without evidence of 
disease 
o Adequately treated carcinoma in situ without 
evidence of invasive disease 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.  


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IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute 
Scientific Review Committee, the Stanford IRB, and has finalized financial and 
contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.  
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 


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Appendix B:  Secondary criteria to continue to ibrutinib treatment 
Protocol Title: 
A Phase 2 Study of Ibrutinib After Reduced-Intensity 
Conditioning and Allogeneic Hematopoietic Cell 
Transplantation for Acute Leukemia 
Protocol Number: 
IRB-38934  /  BMT302 
Principal Investigator: 
Andrew R Rezvani, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC-Approved 
 IRB-Approved 
 Contract signed 
 
IV.  Continuation Criteria 
 
Continuation Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Between Day +60 and Day +90 after allogeneic 
HCT 
 
 
      
2. Age ≥ 18 years 
 
 
      
 
 
 
 
3. Adequate hematologic function, defined as ANC 
> 0.75 x 109/L, platelet count > 50 x 109/L, and 
hemoglobin > 8.0 g/dL without transfusion or 
growth-factor support for at least 7 days prior to 
screening (with the exception of pegylated G-CSF 
and darbepoietin, which require at least 14 days of 
abstinence before screening) 
 
 
      
4. Adequate hepatic and renal function, defined by 
serum AST and ALT ≤ 3x upper limit of 
normal (ULN); estimated creatinine clearance 
≥ 30 mL/min by Cockroft-Gault equation; and 
bilirubin ≤ 1.5 x ULN (unless elevated bilirubin is 
due to Gilbert’s syndrome or of non-hepatic origin) 
 
 
      
5. Adequate coagulation studies, defined as PT/INT 
and PTT (aPTT) ≤ 1.5 x upper limit of normal 
 
 
      
6. Female subjects who are of non-reproductive 
potential (ie, post-menopausal by history - no 
menses for ≥ 1 year; OR history of hysterectomy; 
OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy).  Female subjects of 
childbearing potential must have a negative serum 
pregnancy test upon screening. 
 
 
 
      


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Continuation Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
7. Male and female subjects who agree to use both a 
highly effective method of birth control 
(eg, implants, injectables, combined oral 
contraceptives, some intrauterine devices [IUDs], 
sexual abstinence, or sterilized partner) and a 
barrier method (eg, condoms, vaginal ring, sponge, 
etc) during the period of therapy and for 30 days 
after the last dose of study drug for females and 
90 days after the last dose of the study drug for 
males. 
 
 
 
      
 
Withdrawal Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Active and uncontrolled acute GvHD Grades III or 
IV 
 
 
      
2. Use of secondary therapy for acute GvHD at any 
time (defined as any systemic therapy intended to 
treat acute GvHD besides corticosteroids) 
 
 
      
3. Requirement for anticoagulation with warfarin or 
other Vitamin K antagonists (concomitant use of 
other anticoagulants is permitted) 
 
 
      
4. Relapsed leukemia (> 5% leukemic blasts in 
peripheral blood or bone marrow at any point after 
allogeneic HCT) 
 
 
      
5. Karnofsky Performance Status <60% 
 
 
      
6. Chemotherapy ≤ 21 days prior to first study drug 
dose and/or monoclonal antibody ≤ 6 weeks prior 
to first study drug dose 
 
 
      
7. Vaccinated with live, attenuated vaccine within 
4 weeks of first study drug dose 
 
 
      
8. Currently active, clinically significant cardiovascular 
disease (eg, NYHA Class III or IV heart failure, 
uncontrolled arrhythmia, or acute coronary 
syndrome within 6 months of first study drug dose) 
 
 
      
9. History of stroke or intracranial hemorrhage within 
6 months of first study drug dose 
 
 
      
10. Any life-threatening illness, medical condition, or 
organ dysfunction that, in the investigator’s 
judgement, could compromise the subject’s safety 
or put the study outcomes at undue risk. 
 
 
      
11. Major surgery within 4 weeks of first study drug 
dose 
 
 
      
12. Active, uncontrolled systemic infection 
 
 
      


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Withdrawal Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
13. Unresolved toxicities from prior anti-cancer therapy 
(not resolved to CTCAE v4 Grade 1 or less, or to 
the levels described in these criteria, except 
alopecia) 
 
 
      
14. Unable to swallow capsules or malabsorption 
syndrome, disease significantly affecting 
gastrointestinal function, or resection of the 
stomach or small bowel, symptomatic inflammatory 
bowel disease or ulcerative colitis, or partial or 
complete bowel obstruction 
 
 
 
      
15. Requiring treatment with strong CYP3A inhibitor 
(see Appendix E) 
 
 
      
16. Unwilling or unable to participate in all required 
study evaluations and procedures 
 
 
      
17. Unable to understand the purpose and risks of the 
study and to provide a signed and dated informed 
consent form (ICF) and authorization to use 
protected health information (in accordance with 
national and local subject privacy regulations). 
 
 
      
18. Lactating or pregnant 
 
 
      
19. Uncontrolled cardiac arrhythmias 
 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.  


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IV.  Statement of Continuation Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute 
Scientific Review Committee, the Stanford IRB, and has finalized financial and 
contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.  
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 


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Appendix C:  Grading of acute graft--vs-host disease  
Organ 
Stage 
Description 
Skin 
1 
Maculopapular rash over <25% of body area 
2 
Maculopapular rash over 25–50% percent of body area 
3 
Generalized erythroderma 
4 
Generalized erythroderma with bullous formation and often with 
desquamation 
Liver 
1 
Bilirubin 2.0–3.0 mg/dL; SGOT 150–750 IU 
2 
Bilirubin 3.1– 6.0 mg/dL 
3 
Bilirubin 6.1–15.0 mg/dL 
4 
Bilirubin > 15.0 mg/dL 
Gut 
1 
Diarrhea > 500 mL/day; or upper-gut symptoms with positive histology 
2 
Diarrhea > 1000 mL/day 
3 
Diarrhea > 1500 mL/day 
4 
Diarrhea > 2000 mL/day; or severe abdominal pain ± ileus 
Glucksberg Grade: 
I 
Stage 1 or 2 skin involvement; no liver or gut involvement; ECOG PS 0 
II 
Stage 1–3 skin involvement; Stage 1 liver or gut involvement; ECOG PS 1 
III 
Stage 2–3 skin, liver, or gut involvement; ECOG PS 2 
IV 
Stage 1–4 skin involvement; Stage 2–4 liver or gut involvement; ECOG PS 3 
 
Abbreviations:  SGOT:  serum glutamic oxaloacetic transaminase; ECOG:  Eastern 
Cooperative Oncology Group; PS:  performance status. 


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Appendix D:  Assessment of chronic graft--vs-host disease 
 
Assessment of chronic GvHD will be performed using the 2015 NIH consensus criteria 
(23).  The diagnosis of chronic GvHD requires at least 1 diagnostic manifestation of 
chronic GvHD or at least 1 distinctive manifestation plus a pertinent biopsy, laboratory, 
or other tests (eg, pulmonary function tests [PFT], Schirmer’s test), evaluation by a 
specialist (ophthalmologist, gynecologist), or radiographic imaging showing chronic 
GvHD in the same or another organ, unless stated otherwise. 
The follow table describes the diagnostic, distinctive, other features, or features 
common to both acute and chronic GvHD: 


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Assessment of chronic GvHD will be performed only if a subject has a diagnosis of 
chronic GvHD.  Organ systems will be scored as outlined in the following table: 
 
 
 


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Appendix E:  Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A are defined as follows.  A comprehensive list of inhibitors can be found at 
the following website:  http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below.  Refer to Section 6 on instructions for concomitant use of CYP3A inhibitors and inducers 
with ibrutinib. 
 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin 
glucocorticoids 
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
suboxone 
pioglitazone 
telithromycin 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole 
 
imatinib 
 


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Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
 


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Appendix F.  Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34 to 50 (2 to 3) 
> 50 (> 3) 
Serum albumin, g/L (g/dL) 
> 35 
(> 3.5) 
28 to 35 (2.8 to 3.5) 
< 28 (< 2.8) 
PT INR 
<1.7 
1.71 to 2.30 
> 2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I or II (or 
suppressed with 
medication) 
Grade III or IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
1. Child CG, Turcotte JG.  “Surgery and portal hypertension”. In Child CG.  The liver 
and portal hypertension.  Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R.  “Transection of 
the oesophagus for bleeding oesophageal varices”.  The British journal of 
surgery, 1973;60:646-649. 

ICF_000.pdf: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 1 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
Are you participating in any other research studies? _____ Yes _____No 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of a medication called ibrutinib.  
We hope to learn whether this medication can help to cure leukemia after a blood 
stem cell transplant.  You were selected as a possible participant in this study 
because you are going to have a blood stem cell transplant to treat acute 
leukemia. 
 
Ibrutinib is a medication that blocks specific cell growth signals. It is a pill that is 
taken once a day. It is currently approved by the US Food & Drug Administration 
(FDA) to treat some kinds of leukemias and lymphomas, but is not currently 
approved by the FDA to prevent leukemia from coming back and to prevent GVHD 
after a blood stem cell transplant. Preliminary research suggests that ibrutinib 
might help to keep acute leukemia cells from growing, prevent graft-vs.-host 
disease (GVHD) after a transplant, and help the transplanted donor cells work 
better against leukemia. However, these possible benefits have not yet been 
confirmed in clinical trials. The purpose of this trial is to determine whether 
ibrutinib can help a) prevent leukemia from coming back, and b) prevent GVHD 
and other complications after a blood stem cell transplant. 
 
The following information is provided in order to help you decide whether to 
participate in this clinical trial of ibrutinib. Please read the form carefully, and bring 
up any questions with your doctor and treatment team. Before you decide 
whether to participate, it is important to feel comfortable that you understand the 
possible risks and benefits of this clinical trial. 
 
The choice to participate in this clinical trial is up to you. You may take home a 
copy of this form to think about or to discuss with your family or friends before 
deciding. If you do decide to participate, you will also be given a signed copy of 
this document to take home with you. 
 
If you decide to terminate your participation in this study, you should notify Dr. 
Andrew Rezvani or the study staff at(xxx)-xxx-xxxx. 
 
This research study is looking for 45 people who are having blood stem cell 
transplants to treat acute leukemia. Several other cancer centers are 
participating in this study. Stanford University expects to enroll 25 research study 
participants.  
 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 2 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to 
participate will not have any negative effect on you or your medical care.  You 
can decide to participate now, but withdraw your consent later and stop being in 
the study without any loss of benefits or medical care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT  
 
This research study will take a total of 2 years of participation. Participants will 
take ibrutinib for 18 months, starting at about 2 months after their blood stem 
cell transplant. Medical information will be collected for 2 years after the blood 
stem cell transplant as part of this study. After the study ends, their regular 
doctors will continue to follow them. 
 
PROCEDURES 
 
If you choose to participate, you will have screening procedures done before 
your transplant to make sure that you meet the requirements to be in this study. 
If you test positive for HIV, counseling will be provided. If you meet all study 
requirements, you will be enrolled in the study. Your actual blood stem cell 
transplant will be done according to standard practices. Your transplant itself, 
including the chemotherapy drugs, donor choice, and other medications, will not 
be affected by this trial and will not contain any experimental treatments. 
 
You will be assessed again between 1 and 2 months after your blood stem cell 
transplant to make sure that you remain eligible to receive ibrutinib, which is the 
experimental drug in this study. If you are not eligible, then you will not receive 
ibrutinib, and the rest of your transplant care will be provided according to 
normal standards of care. If you remain eligible, then you will begin taking 
ibrutinib, which is the experimental drug in this study, between 2 and 3 months 
after your transplant. 
While taking the study drug (ibrutinib), you will be monitored closely by your 
transplant doctor. The dose of ibrutinib may be adjusted by your transplant 
doctor to prevent interactions with other medications, and the study drug may 
be temporarily or permanently stopped if you experience side effects. This study 
will track side effects from ibrutinib, and the study will be stopped if there is 
evidence that ibrutinib is causing increased risks. 
Other than taking ibrutinib (the study drug), the rest of your transplant care, 
testing, and follow-up will be provided according to normal standards of care. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 3 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
The only other research procedures as part of this study will involve blood draws 
when you start chemotherapy before your transplant, when you start taking 
ibrutinib, and again at 6 months, 1 year, and 18 months after your blood stem 
cell transplant. For each draw, a sample (up to 3-5 tablespoons) will be collected. 
Whenever possible, we will try to combine these blood draws with other blood 
draws that you will be having as part of your regular medical care. These blood 
samples may be sent outside of Stanford for analysis. The results will not directly 
affect your medical care, but may be used to help understand the effects of 
ibrutinib and to help develop new studies in the future. Any of your samples 
which are used in research may result in new products, tests or discoveries. In 
some instances, these may have potential commercial value and may be 
developed and owned by the Investigators, Stanford University and/or others.  
However, donors of samples do not retain any property rights to the materials.  
Therefore, you would not share in any financial benefits from these products, 
tests or discoveries. Any samples left over when the study is completed will not 
be saved for future research.  
 
Reproductive effects  
 
The effects of ibrutinib on a developing baby are unknown, so women who are 
pregnant or nursing are not allowed to be in this study. Nobody knows what 
these risks are right now. Some drugs cause women to have their babies 
prematurely (early) or to have babies with birth defects.  
 
If you are able to have children, you must use a highly effective method of birth 
control while taking study treatment and also a barrier method, as well as for 1 
month (women) or 3 months (men) after you stop taking study treatment, to 
prevent pregnancy in either you or your partner. A “highly effective method of 
birth control” is defined as a method that has a low failure rate (ie, less than 1% 
per year) when used consistently and correctly and includes implants, 
injectables, birth control pills with 2 hormones, some intrauterine devices (IUDs), 
sexual abstinence (which is defined as refraining from all aspects of sexual 
activity) or a sterilized partner. A barrier method of contraception (eg, condoms 
with spermicide, cervical rings, sponge, etc) must be used.  
Note: Some birth control pills may not work when you are taking certain drugs. 
If you have any questions about this, please discuss this with the study doctor.  
 
Be aware that you can still become pregnant even if you use a highly effective 
method of birth control.  
 
Men: If your partner becomes pregnant while you are on study treatment, or 
within 3 months of your last dose of ibrutinib, you must notify the study staff. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 4 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
The study staff will discuss this with you further. You should not donate sperm 
while you are taking the study drug and for 3 months after you stop taking the 
study drug. If your female partner becomes pregnant during your participation in 
the study you MUST notify your study doctor immediately. The Sponsor will ask 
your female partner for permission to collect information about the pregnancy 
and the birth of your baby even after study treatment is stopped for any reason. 
 
Women: If you become pregnant while you are on study treatment or within 1 
month of your last dose of ibrutinib you must notify the study staff. If you 
become pregnant on the study, you must immediately stop taking the study 
treatment. The Sponsor Investigator will continue to collect information about 
your pregnancy and the birth of your baby even after study treatment is 
stopped.  
 
Breast-feeding 
It is not known whether ibrutinib or its metabolites are excreted in human milk. 
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants from ibrutinib, breast-feeding should 
be discontinued during ibrutinib treatment. 
 
TISSUE SAMPLING FOR FUTURE RESEARCH 
Research using tissues is an important way to try to understand human disease 
and how immune responses cure blood cancers and cause problems such as 
graft versus host disease. You have been given this information because the 
investigators want to include your tissue in a research project and because they 
want to save the samples for future research.  There are several things you 
should know before allowing your tissues to be studied. 
You will be identified only by a unique code number.  Information about the code 
will be kept in a secure location and access limited to research study personnel.   
You have the right to refuse to allow your tissues to be studied now or saved for 
future study.  You may withdraw from this study at any time.  The investigators 
might retain the identified samples, e.g., as part of your routine clinical care, but 
not for additional research. 
 
You will be told the results of test that are part of your clinical care, but you will not 
be told the results of the research tests, including any future research tests. 
 
I allow a sample of my tissues to be taken for research use 
           
I DO NOT allow a sample of my tissues to be taken research use      
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 5 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include: 
• Follow the instructions of the Protocol Director and study staff. 
• Take the study drug as instructed. 
• Keep your study appointments.  If it is necessary to miss an appointment, 
please contact the Protocol Director or research study staff to reschedule 
as soon as you know you will miss the appointment. 
• Tell the Protocol Director or research study staff about any side effects, 
doctor visits, or hospitalizations that you may have. 
• Tell the Protocol Director or research staff if you believe you might be 
pregnant or gotten your partner pregnant. 
• Keep the study drug in a safe place, away from children and for your use 
only. 
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about 
staying in the study. 
 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your 
decision will not affect your ability to receive medical care for your disease and 
you will not lose any benefits to which you would otherwise be entitled.  
 
If you decide to withdraw your consent to participate in this study, you should 
notify Dr. Andrew Rezvani at (xxx)-xxx-xxxx. 
 
If you withdraw from the study, or the study medication is stopped for any 
reason, we will no longer collect your information for the study, and you will be 
asked to return all study-related medication (ibrutinib). 
 
The Protocol Director may also withdraw you from the study and the study 
medication may be stopped without your consent for one or more of the 
following reasons:  
o Failure to follow the instructions of the Protocol Director and 
study staff. 
o The Protocol Director decides that continuing your 
participation could be harmful to you. 
o Pregnancy  
o You need treatment not allowed in the study. 
o Your leukemia comes back despite taking ibrutinib. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 6 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
o The study is cancelled.  
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
You may develop side effects while participating in this study. You should tell the 
study doctor about any side effects that you develop.  
 
The side effects listed below have been reported by patients who have received 
ibrutinib in clinical trials.  
 
If you experience serious problems, you may be asked to return to the study 
center for more tests.  If you experience the following symptoms of an allergic 
reaction, contact the Study Doctor or the Study Team immediately.  If you are in 
distress, CALL 911 immediately.  
• Allergic reaction, including rash, hives and/or itching of the skin, or blisters;  
increased heart rate (a fast pulse or tachycardia);  and/or abnormal or 
increased sweating  
• Swelling of the face, mouth, lips, gums, tongue and/or neck 
• Wheezing;  shortness of breath;  or difficulty breathing  
• Dizziness;  confusion;  feeling light-headed;  pounding or racing heart;  and/or 
fainting  
• Fever;  chills;  weakness;  confusion;  body aches;  cold or flu symptoms; 
and/or feeling tired 
• Easy bruising and/or bleeding 
• Sudden severe headaches;  weakness in the arms or legs;  difficulty speaking 
or understanding speech;  and/or loss of balance 
• Yellowing of the eyes and skin (jaundice), dark-colored urine;  and/or gray- or 
clay-colored bowel movement (stools);   
• Upset stomach (nausea), loss of appetite;  tiredness (fatigue);  and/or diarrhea 
• Severe skin reactions and/or rash with blisters and peeling skin or spreads 
quickly, which may include open ulcers or sores in the mouth and other areas 
of the body  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 7 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
Most Common Side Effects of the Study Drug Ibrutinib  
[these side effects occurred in more than 1 in 5 people taking ibrutinib  
(more than 20%)]   
• Occurrence or increase in frequency of loose or watery stools (Diarrhea) 
• Muscle and joint pain (musculoskeletal pain) 
• Nausea 
• Low white blood cell count (WBC, blood cells that help fight infection) 
(neutropenia) 
• Low Platelet count (cells that help blood to clot) (Thrombocytopenia) 
• Bleeding (Haemorrhage) 
• Rash  
• Fever (pyrexia) 
• Common cold (Upper Respiratory Tract Infection) 
Less-likely Side Effects (these side effects occurred in  
more than more than 1 in 10 people taking ibrutinib (10% to 20%)  
• Lung infection (pneumonia)  
• Sores in the mouth (stomatitis)  
• Skin infection  
• High blood pressure (hypertension)  
• Headache  
• Joint aches (arthralgia) 
• Vomiting  
• Constipation  
• Weakness, tingling, numbness, and pain from nerve damage, usually in the 
hands and feet (peripheral neuropathy) 
• Dizziness  
• Swelling of the hands or feet (peripheral edema)  
• Urinary tract infection (UTI) 
• Muscle spasms  
Unlikely Side Effects (these side effects occurred in  
more than 1% to 10% of people taking ibrutinib) 
• Sinus infection (sinusitis) 
• Non-melanoma skin cancer 
• Severe infection throughout the body (sepsis)  
• Inflammation within the lungs that may lead to permanent damage 
(Interstitial lung disease) 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 8 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
• Abnormal heart rhythm (atrial fibrillation)  
• Increased level of uric acid in the blood (hyperuricemia) 
• Low white blood cell count (WBC, blood cells that help fight infection) with 
fever (febrile neutropenia)  
• Increase in specific white blood cell count (Leukocytosis,Lymphocytosis) 
• Blurry vision 
• Skin redness (erythema)  
• Fingernails or toenails breaking (onychoclasis) 
• Increased level of “creatinine” in the blood (blood creatinine increased) 
• Heart failure, which makes you short of breath and may lead to swollen legs 
 
Unlikely Side Effects (these side effects occurred in  
less than 1% of people taking ibrutinib) 
• High levels of cancer cell breakdown products, which may lead to changes in 
kidney function, abnormal heartbeat, or seizures (Tumor lysis syndrome) 
• Liver failure (hepatic failure)  
• Inflammation of the fatty tissue underneath the skin (Panniculitis) 
• High WBC count with abnormal clumping that can lead to bleeding 
(leukostasis syndrome) 
• Severe rash with blisters and peeling skin, particularly around the mouth, nose, 
eyes and genitals (Stevens-Johnson syndrome)  
• Abnormal rapid and/or irregular heart rhythm that starts from the lower 
chambers (ventricles) of the heart (Ventricular tachyarrhythmias)  
• Swollen face, lip, mouth, tongue or throat (angioedema) 
• Itchy rash (urticaria)  
• Temporary or permanent decrease of brain or nerve function due to reduced 
blood flow to the brain (mini-stroke or stroke) 
Serious Side Effects of Ibrutinib – Contact your study doctor 
IMMEDIATELY.  
Some reactions to ibrutinib can be serious or even fatal.  If any of the events 
below happen, contact your Study Doctor immediately to help prevent the 
event from getting worse.  If the event gets worse or you are in distress, 
CALL 911.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 9 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
Effects on the heart 
Abnormal rapid and/or irregular heart rhythm (atrial fibrillation, atrial flutter, 
and/or ventricular tachyarrhythmia with some fatal events) have been reported 
in patients treated with ibrutinib especially when they also have had 
heart conditions; increased blood pressure; infections; or an abnormal heartbeat 
in the past.  Atrial fibrillation/flutter is a common type of abnormal heartbeat.  
The heartbeat may be fast or irregular causing symptoms such as a pounding or 
racing heart; dizziness; weakness; feeling light-headed; shortness of breath, 
chest discomfort or fainting.  You should seek medical attention and notify your 
Study Doctor immediately if you develop any of these symptoms while 
receiving the study drug. 
Interstitial lung disease (ILD)  
Interstitial lung disease is a group of lung disorders in which the tissues become 
inflamed and may become damaged.  Interstitial lung disease is not associated 
with infections (eg, bacteria, viruses, fungi) and has been reported in patients 
treated with ibrutinib.  You should report to your physician if you have cough; or 
any signs of new or worsening respiratory symptoms, such as shortness of 
breath or difficulty breathing.  
Infections 
You may experience viral, bacterial, or fungal infections during treatment with 
ibrutinib.  Some of these infections have been associated with hospitalization and 
death.  Contact your study doctor immediately if you have fever;  chills;  
weakness;  confusion;  body aches;  cold or flu symptoms;  vomiting; jaundice; 
feel tired;  or feel short of breath.  These could be signs of a serious infection. 
Your study doctor may start or continue medication to help prevent or treat an 
infection.  
A rare and usually fatal viral disease in the brain, progressive multifocal 
leukoencephalopathy (PML), has been reported in patients treated with ibrutinib 
in combination with rituximab and in patients who were previously treated with 
rituximab.  If you experience symptoms such as weakness, paralysis, vision loss 
and/or impaired speech, you should seek medical attention immediately and also 
tell your Study Doctor. 
Bleeding effects  
You may experience bruising or bleeding during treatment with ibrutinib.  Rarely, 
serious or fatal internal bleeding may occur, such as bleeding in your stomach, in 
your intestine, or in or around your brain, sometimes resulting in death.  If you 
take other medicines or supplements that increase your risk of bleeding (such as 
aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or medicines used to 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 10 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
prevent or treat blood clots or stroke) ibrutinib may increase this risk.  Blood 
thinners such as warfarin or other vitamin K antagonists should not be taken 
together with ibrutinib.  Supplements such as fish oil and vitamin E preparations 
should be avoided while taking ibrutinib.  
Seek medical attention immediately and also call your Study Doctor if you have 
signs or symptoms of severe bleeding in or around the brain such as sudden 
severe headaches; weakness in the arms or legs; difficulty speaking or 
understanding speech; or loss of balance.  You should also seek medical 
attention immediately and notify your Study Doctor if you have signs or 
symptoms of serious bleeding, such as blood in your stools or urine or bleeding 
that lasts for a long time or that you cannot control. 
Decreased blood counts  
Severe decreases in white blood cells, red blood cells, and platelets (neutropenia, 
anemia, and thrombocytopenia) were reported in subjects treated with ibrutinib.  
If you experience symptoms such as fever; weakness; or easy bruising and/or 
bleeding; you should tell your Study Doctor immediately and seek medical 
attention.  
Liver Failure 
Rare cases of liver failure have been reported in patients treated with ibrutinib.  
Symptoms of liver failure include yellowing of the eyes and skin (jaundice), 
itching of the skin, dark-colored urine; gray-or clay-colored bowel movement  
(stools); confusion;  Upset stomach (nausea), loss of appetite; tiredness 
(fatigue); or diarrhea.  You should tell your study doctor immediately if you 
have any of these symptoms which may suggest liver disease.  Your Study 
Doctor may be able to diagnose and provide you required medical care.  
Allergic reactions  
Sometimes people have allergic reactions to drugs.  Serious allergic reactions can 
be life-threatening.  If you have an allergic reaction to ibrutinib or the other 
study medications (idarubicin or cytarabine), you might develop a rash;  
difficulty breathing;  wheezing when you breathe;  sudden low blood pressure 
with light-headedness;  swelling around the mouth, throat or eyes;  a racing 
heartbeat;  and/or abnormal or increased sweating.  Before starting the study 
drug, you must tell your Study Doctor about any drug allergies.  You should tell 
the Study Doctor immediately if you have any allergy symptoms listed above.  
Rash 
A maculopapular rash (flat, red areas on the skin with small bumps) has been 
commonly reported in patients treated with ibrutinib alone or in combination with 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 11 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
other drugs.  Most rashes are mild to moderate in severity and begin 2 to 3 
weeks or longer after starting ibrutinib.   
There have been rare reports of severe skin reactions (known as severe 
cutaneous adverse reaction or “SCAR,” involving more than 50% of the body), or 
rash with blisters and peeling skin, which may include open ulcers or sores in the 
mouth and other areas of the body (Stevens-Johnson Syndrome).  These skin 
rashes could be life-threatening.  You should notify your Study Doctor 
immediately if you develop a rash that spreads quickly, or if you notice peeling 
of your skin, with or without ulcers or sores in your mouth. 
Interference with other drugs  
Some juices or foods like grapefruit and Seville oranges, as well as some 
medications, may interfere with the way your body processes ibrutinib.  This 
interference could cause the amount of ibrutinib in your body to be higher or 
lower than expected.  It is also possible that taking the study drug with your 
regular medications or supplements, including fish oil, Vitamin E, or other 
vitamins, may change how your regular medications, or your regular 
supplements, work.  It is very important that you avoid grapefruit juice and 
Seville oranges and tell the Study Doctor about all medications, supplements, or 
herbal medicine like St John’s wort that you are taking during the study.  You 
should notify your Study Doctor immediately about any side effects to avoid 
possible harm.  
Other Serious Side Effects of Ibrutinib  
Lymphocytosis and leukostasis (increases in WBC) 
You may experience an increase in the number of lymphocytes, which is a 
specific type of white blood cell, in your blood (lymphocytosis).  This may occur 
in the first few weeks of treatment and you should not assume that this increase 
in white blood cells means that your disease is worsening.  This increase may 
last for several weeks to months.  In rare cases, increased number of white 
blood cells in your bloodstream may change the blood flow resulting in bleeding 
or clotting (leukostasis).  Isolated cases of these events have been reported in 
patients treated with ibrutinib.  Your Study Doctor will monitor your blood counts 
and may administer additional therapy as needed.  Talk to your Study Doctor 
about what your test results mean.  
Tumor Lysis Syndrome (TLS) 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer 
cells have happened during treatment of cancer and sometimes even without 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 12 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
treatment.  This may lead to changes in kidney function, abnormal heartbeat, or 
seizures.  Your Study Doctor may do blood tests to check for TLS. 
High blood pressure (hypertension)  
High blood pressure, also called hypertension, has been commonly-reported in 
subjects treated with ibrutinib.  Sometimes people with high blood pressure may 
have headaches; dizziness;  nervousness;  sweating;  difficulty in sleeping;  facial 
flushing or nosebleeds;  but in some cases, there may be no symptoms and it 
may go undetected.  After starting ibrutinib, your doctor may measure your 
blood pressure regularly.  You should let your study doctor know if you have any 
of the symptoms of high blood pressure, which may mean that you have 
developed hypertension or that your hypertension is getting worse.  Your study 
doctor may adjust existing anti-hypertensive medications and/or start anti-
hypertensive therapy as appropriate.  
Stroke 
Cases of stroke, with and without changes in heartbeat rhythm and/or 
hypertension have been reported with the use of ibrutinib.  Some of these cases 
have led to death. Seek immediate medical attention if you notice or someone 
notices in you: sudden numbness or weakness in the limbs (especially on one 
side of the body), sudden confusion, trouble speaking or understanding speech, 
sight loss, difficulty walking, loss of balance or lack of coordination, sudden 
severe headache with no known cause. These may be signs and symptoms of 
stroke. 
Other Cancers 
Other cancers have been observed in patients who have been treated with 
ibrutinib and with chemotherapy (such as idarubicin).  These include, skin 
cancer, solid tumors, and blood cancers.  The causal relationship with ibrutinib is 
unknown.  You should tell your Study Doctor if you develop a new cancer while 
in the study.  
Drug interruption for any surgical procedures  
Ibrutinib may increase the risk of bleeding with any surgical procedure.  Ibrutinib 
should be held at least 3 to 7 days before and after surgery depending upon the 
type of surgery and the risk of bleeding.  For emergency surgical procedures, 
ibrutinib should be discontinued (stopped) after the procedure until the surgical 
site is reasonably healed (not oozing fluid).  
Please contact your Study Doctor if you have any surgical procedures and your 
Study Doctor will tell you when to stop ibrutinib and when to restart it following 
a surgical procedure.  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 13 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
Please contact your study doctor as soon as possible and your study doctor will 
tell you when to stop ibrutinib and when to restart it following a surgical 
procedure. 
 
In addition to the risks listed above, there could be unknown or unexpected side 
effects associated with the use of ibrutinib. You will be told in a timely manner, 
verbally and in writing, of any new information, findings, or changes to the way 
the research will be done that might influence your willingness to continue your 
participation in this study.  
 
You may have all, some, or none of the listed side effects of ibrutinib. Your study 
doctors and nurses will check you closely for side effects. You may receive 
medicines or other treatments to prevent or reduce some of these effects. Please 
tell the study doctor or study staff right away if you have any side effects. Please 
tell them if you have any other problems with your health or the way you feel 
during the study, whether or not you think they are related to the study drug.  
 
You should get medical help and contact the study doctor or study staff if you 
have any of these or any other side effects during the study.  
 
Any study drug can also have side effects that are unexpected or unforeseen. 
You will be monitored for any possible side effects during this study. 
 
POTENTIAL BENEFITS                              
 
There are several potential benefits of taking ibrutinib after a blood stem cell 
transplant. These possible benefits are based on studies that have been done in 
the laboratory or in people being treated for other diseases. The possible 
benefits of taking ibrutinib after your transplant include: 
 
• The possibility that ibrutinib will help cure your leukemia and keep it from 
coming back. 
• The possibility that ibrutinib will help the transplanted donor cells work 
better to get rid of your leukemia. 
• The possibility that ibrutinib will help prevent graft-vs.-host disease 
(GVHD), one of the most serious possible complications of a blood stem 
cell transplant. 
 
This clinical trial is designed to determine whether ibrutinib has these benefits. 
Because these possible benefits are based on preliminary research, we cannot 
and do not guarantee or promise that you will receive any benefits from this 
study. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 14 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
 
ALTERNATIVES 
 
The alternative to participating in this trial is to receive your transplant according 
to the normal standard of care, without taking ibrutinib. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell 
the Protocol Director.   
 
You will be told of any important new information that is learned during the 
course of this research study, which might affect your condition or your 
willingness to continue participation in this study. 
 
ClinicalTrials.gov 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web site will not 
include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals.  Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as 
required by law.  However, there is always some risk that even de-identified 
information might be re-identified.  
 
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect 
research records and learn your identity if this study falls within its jurisdiction. 
 
The purpose of this research study is to obtain data or information on the safety 
and effectiveness of ibrutinib; the results will be provided to the study supporter, 
Pharmacyclics LLC, its affiliates and its collaborators (Janssen Biotech, Inc.), the 
Food and Drug Administration and other federal and regulatory agencies as 
required. 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 15 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
Pharmacyclics LLC, its affiliates, and its collaborators (Janssen Biotech, Inc.) 
may study your data and tissue, blood, or other specimens collected from you. 
Your tissue, blood or other specimens may be used for any purpose including 
research, which may lead to the development of medical products such as 
devices, or new drugs or patentable processes and procedures. You will not be 
compensated for any patents or discoveries that may result from your 
participation in this research. Your signature on this form indicates that you 
understand and accept this. 
 
CERTIFICATE OF CONFIDENTIALITY 
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. The researchers with this Certificate may not disclose or use 
information, documents, or biospecimens that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other action, suit, or 
proceeding, or be used as evidence, for example, if there is a court subpoena, 
unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or 
local law that requires disclosure (such as to report child abuse or communicable 
diseases but not for federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, see below); if you have consented to the 
disclosure, including for your medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research subjects. 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 16 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
 
Authorization To Use Your Health Information 
For Research Purposes 
 
Because information about you and your health is personal and 
private, it generally cannot be used in this research study without 
your written authorization.  If you sign this form, it will provide that 
authorization.  The form is intended to inform you about how your 
health information will be used or disclosed in the study.  Your 
information will only be used in accordance with this authorization 
form and the informed consent form and as required or allowed by 
law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my 
health information be utilized in the study? 
This clinical trial is being done to determine whether the medication 
ibrutinib can help cure leukemia after a blood stem cell transplant. 
Your health information may be used to help answer this question as 
part of the study, and may be used in publications or presentations in 
the medical literature. The information gained in this study may also 
be reviewed by Stanford University study sponsor, Pharmacyclics 
study supporter,and to the US Food & Drug Administration (FDA). 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, 
you will not be able to participate in this research study, including 
receiving any research-related treatment. Signing the form is not a 
condition for receiving any medical care outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your 
authorization regarding the use and disclosure of your health 
information (and to discontinue any other participation in the study) 
at any time.  After any revocation, your health information will no 
longer be used or disclosed in the study, except to the extent that 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 17 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
the law allows us to continue using your information (e.g., necessary 
to maintain integrity of research).  If you wish to revoke your 
authorization for the research use or disclosure of your health 
information in this study, you must write to: Andrew R. Rezvani, 
M.D., 300 Pasteur Drive, MC 5623, Stanford, CA 94305. 
 
What Personal Information Will Be Obtained, Used or 
Disclosed? 
Your health information related to this study, may be used or 
disclosed in connection with this research study, including, but not 
limited to, your medical condition, any complications of the study 
drug or of your transplant, blood test results, imaging studies or 
reports, pathology reports, and physical examination results.  
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your 
health information in connection with this research study: 
• The Protocol Director (Andrew R. Rezvani, M.D.) 
• The Stanford University Administrative Panel on Human 
Subjects in Medical Research and any other unit of Stanford 
University as necessary 
• Research Staff 
• The Data Safety Monitoring Committee at the Stanford Cancer 
Institute 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your 
health information to the following persons and organizations for 
their use in connection with this research study:  
• The Office for Human Research Protections in the U.S. 
Department of Health and Human Services 
• The study supporter Pharmacyclics LLC, its affiliates, and its 
collaborators (e.g. Janssen Biotech, Inc) 
• The Food and Drug Administration 
• The NIH 
• Researchers participating in this study at other institutions 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 18 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
 
Your information may be re-disclosed by the recipients described 
above, if they are not required by law to protect the privacy of the 
information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health 
information will end on December 31, 2025, or when the research 
project ends, whichever is earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have 
access to any health information developed as part of this study until 
it is completed.  At that point, you would have access to such health 
information if it was used to make a medical or billing decision about 
you (e.g., if included in your official medical record).  
 
 
________________________________             
______________ 
Signature of Adult Participant                                 Date 
 
 
_____________________________________             
 
Print Name of Adult Participant                                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 19 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
FINANCIAL CONSIDERATIONS 
 
 
Payment 
You will not be paid to participate in this research study. 
 
 
Costs 
If you participate in this study, the study will pay for those services, supplies, 
procedures, and care associated with the study that are not a part of your 
routine medical care.  However, there may be additional costs to you.  These 
include basic expenses like transportation and the personal time it will take to 
come to the study visits.  You and/or your health insurance must pay for 
services, supplies, procedures, and care that are required during this study for 
routine medical care.  You will also be responsible for any co-payments 
and/or deductibles as required by your insurance.  Participation in this 
study is not a substitute for health insurance.   
 
Support 
Pharmacyclics is providing financial support and/or material for this study. The 
study drugs will be provided to you at no cost to you by Pharmacyclics.   
 
The National Institutes of Health are providing some financial support for the 
facility and staff where part or all of the study is taking place. 
 
Consultative or Financial Relationships 
Dr. Wen-Kai Weng and Miklos are paid advisors to Kite Pharma and Janssen 
Pharma, the company whose products are being used in this study. Dr. Miklos is 
a paid advisor to Pharmacyclics, LLC the company funding this study. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental 
– involve some risk of injury.  In spite of all precautions, you might develop 
medical complications from participating in this study.  If such complications 
arise, the Protocol Director and the research study staff will assist you in 
obtaining appropriate medical treatment.  In the event that you have an injury or 
illness that is directly caused by your participation in this study, reimbursement 
for all related costs of care first will be sought from your insurer, managed care 
plan, or other benefits program.  You will be responsible for any associated 
co-payments or deductibles as required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible for these 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 20 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
costs.  If you are unable to pay for such costs, the Protocol Director will assist 
you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or 
alternative courses of treatment, you should ask the Protocol Director, Andrew R. 
Rezvani, M.D. You may contact him now or later at (xxx)xxx-xxxx.  
 
Injury Notification:  If you feel you have been hurt by being a part of this study, 
please contact the Protocol Director, Andrew R. Rezvani, M.D., at (xxx)-xxx-xxxx.  
 
Independent Contact:  If you are not satisfied with how this study is being 
conducted, or if you have any concerns, complaints, or general questions about 
the research or your rights as a participant, please contact the Stanford 
Institutional Review Board (IRB) to speak to someone independent of the 
research team at (xxx)-xxx-xxxx or toll free at 1-xxx-xxx-xxxx.  You can also 
write to the Stanford IRB, Stanford University, 1705 El Camino Real 
Palo Alto, CA 94306. 
 
Alternate Contact:  If you cannot reach the Protocol Director, please contact Dr. 
David Miklos at (xxx)xxx-xxxx. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant, you have the following rights.  These rights include but 
are not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably 
to be expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices 
that might be advantageous to the subject, their relative risks and 
benefits; 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 21 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
• 
be informed of the avenues of medical treatment, if any available to the 
subject after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or 
the procedures involved;  
• 
be instructed that consent to participate in the medical experiment may 
be withdrawn at any time and the subject may discontinue participation 
without prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a 
medical experiment without the intervention of any element of force, 
fraud, deceit, duress, coercion or undue influence on the subject's 
decision. 
 
 
May we contact you about future studies that may be of interest to you?    
____ Yes  ____ No 
 
Signing your name means you agree to be in this study and that you will receive 
a copy of this signed and dated consent form.  
 
 
 
_____________________________________                ____________ 
Signature of Adult Participant 
 
 
 
   
   Date 
 
 
_____________________________________             
Print Name of Adult Participant                                         
 
 
_____________________________________                ____________  
Signature of Person Obtaining Consent  
 
   
  Date 
 
 
_____________________________________             
Print Name of Person Obtaining Consent 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Andrew Rezvani, MD               ep# 38934 
Protocol Title:    
BMT302 - A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and 
Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia   
 
Page 22 of 22 
 
BMT302 version 7 23 November 2020 
 
Participant ID: 
MRN:  
IRB Use Only 
Approval Date:  December 8, 2020  
Expiration Date: November 24, 2021 
 
 
 
 
 
 
The following witness line is to be signed only if the consent is provided as a summary 
form and accompanied by a short form foreign language consent. 
 
 
 
_____________________________________                     ____________ 
Signature of Witness                                                              Date 
 
 
__________________________________              
Print Name of Witness                                         
(e.g., staff, translator/interpreter, family member) 
• Translated short form must be signed and dated by both the participant (or their LAR) AND 
the witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
− Must be signed by the witness AND the Person Obtaining Consent (POC). 
− The non-English speaking participant/LAR does not sign the English consent. 
− The non-English speaking participant/LAR should not sign the HIPAA participant line 
− If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) 
must ensure that 1) the LAR's Description of Authority is completed and 2) that any 
questions or options presented by the consent form are documented and initialed by the POC 
on the Summary Form, per the participant's wishes, as they are understood during the 
consent process.