Conditions: Lymphoma
Keywords: Lymphoma Blood And Marrow Transplantation Post Autologous Stem Cell Transplantation SCT B-cell lymphoma Ibrutinib PCI-32765 Imbruvica
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if ibrutinib can help to control lymphoma in patients who have had an autologous stem cell transplant (a transplant using your own stem cells). The safety of this drug will also be studied.

Detailed description:
Study Drug Administration:

If you take part in this study, you will take ibrutinib by mouth 1 time each day for up to 3 years. You must swallow the capsules whole with a glass (about 8 ounces) of water. Do not open, break, or chew the capsules. You should take ibrutinib at the same time every day.

If you miss a dose of ibrutinib, take it as soon as you remember on the same day. Take your next dose of ibrutinib at your regular time on the next day. Do not take 2 doses of ibrutinib on the same day to make up for a missed dose.

You will be given a study drug diary to write down what time you take each dose of ibrutinib. You need to bring the study drug diary, any leftover study drug, and any empty study drug containers with you to each visit.

The dose of ibrutinib you receive may be lowered, if the doctor thinks it is needed.

Study Visits:

One (1) time during Weeks 1-4, 6, and 8 and then 1 time each month after that for up to 3 years after your first dose of ibrutinib, blood (about 2 tablespoons) will be drawn for routine tests and to check your kidney and liver function. The blood draws may be performed at MD Anderson or at a lab closer to your home.

If the study doctor thinks it is needed, you may need to have these blood draws more often.

Around 1 month after your first dose of ibrutinib, you will have a bone marrow biopsy/aspirate to check the status of the disease, if the study doctor thinks it is needed. To collect a bone marrow biopsy/aspirate, an area of the hip or other site is numbed with anesthetic, and a small amount of bone and bone marrow is withdrawn through a large needle.

Around 3, 6, 9, and 12 months, then every 6 months for 3 years after your first dose of ibrutinib:

* You will have a physical exam.
* You will have computed tomography (CT) scans to check the status of the disease.
* You will have a bone marrow biopsy/aspirate to check the status of the disease.

Length of Study:

You may continue taking the study drug for up to 3 years. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on this study will be over after about 3 years.

Follow-Up Visit:

You will continue to have the CT scans and blood draws described in the study visits section 1 time a year for up to 3 years.

If you had a positron emission tomography (PET) scan that was performed at the time of your transplant and the scan showed that the disease was still in your body, you will have a PET scan 1 time each year while taking ibrutinib. The PET scan will not be repeated if the results show that there is no disease in the body.

This is an investigational study. Ibrutinib is FDA-approved and commercially available for the treatment of many types of cancers, including mantle cell lymphoma with 1 prior therapy. The use of ibrutinib to treat double hit lymphoma after an autologous stem cell transplant is considered investigational. The study doctor can explain how the study drug is designed to work.

Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Arms:
arm 1: Ibrutinib started at a daily dose of 560 mg by mouth daily for up to 3 years.

Interventions: intervention 1: Ibrutinib
Intervention descriptions: intervention 1: 560 mg by mouth daily.

Protocol document:
Prot_SAP_000.pdf: 
2014-0096 
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Targeting BTK with Ibrutinib after Autologous Stem Cell Transplantation  
in "Double-Hit" B-Cell Lymphoma 
 
Principal Investigator: 
Issa F. Khouri, MD 
 
The University of Texas M. D. Anderson Cancer Center 
 
Stem Cell Transplantation and Cellular Therapy Department 
 
1515 Holcombe Blvd, Unit 0432 
 
Houston, TX  77030 
 
Telephone:  713-745-0049 
 
Fax: 713-794-4902 
 
ikhouri@mdanderson.org 
 
Co-Chairs: 
Joseph Khoury, MD1 
 
James M. Reuben, MD, PhD2 
 
Collaborators: 
Amin Alousi, MD3 
 
Paolo Anderlini, MD3 
Sairah Ahmed, MD3 
 
Qaiser Bashir, MD3 
 
Roland L. Bassett, Jr, MS4 
 
Richard E. Champlin, MD3 
 
Luis Fayad, MD2 
 
Partow Kebriaei, MD3 
 
Yasuhiro Oki, MD2 
 
Amanda L. Olson, MD3 
 
Betul Oran, MD3 
 
Muzaffar H. Qazilbash, MD3 
 
Nina Shah, MD3 
Francesco Turturro, MD2  
 
Jason R. Westin, MD2 
 
1 The University of Texas M. D. Anderson Cancer Center, Hematopathology Department 
2 The University of Texas M. D. Anderson Cancer Center, Lymphoma/Myeloma Department 
3 The University of Texas M. D. Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
4 The University of Texas M. D. Anderson Cancer Center, Biostatistics Department 


2014-0096 
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Table of Contents 
 
 
1.0   
Objectives ...................................................................................................................... 5 
1.1 
Primary objective ........................................................................................................ 5 
1.2 
Secondary objectives .................................................................................................. 5 
1.3  
Tertiary objectives ....................................................................................................... 5 
2.0   
Background .................................................................................................................... 5 
2.1  
Oncogenes involved in DHL ........................................................................................ 5 
2.2  
Morphology and Immunophenotyping ......................................................................... 5 
2.3  
Clinical Features ......................................................................................................... 6 
2.4  
Rationale for Stem Cell Transplantation (SCT) ........................................................... 7 
2.5  
Targeting B-cell receptor ............................................................................................. 7 
2.6  
Rationale for maintenance ibrutinib after stem cell transplantation in DHL .................. 8 
2.7  
Correlative studies ...................................................................................................... 8 
2.8  
Ibrutinib ....................................................................................................................... 9 
2.8.1  
Background ......................................................................................................... 9 
2.8.2  
Summary of Nonclinical Data ............................................................................... 9 
2.8.3  
Pharmacology .................................................................................................... 10 
2.8.4   
Toxicology ......................................................................................................... 10 
2.8.5  
Carcinogenesis, Mutagenesis, Impairment of Fertility ........................................ 10 
2.8.6  
Summary of Clinical Data................................................................................... 11 
2.8.7  
Pharmacokinetics and Product Metabolism ....................................................... 11 
2.8.8  
Ibrutinib safety profile ......................................................................................... 11 
3.0 
Patient Eligibility ........................................................................................................... 15 
3.1   
Inclusion Criteria .................................................................................................... 15 
3.2  
Exclusion Criteria ...................................................................................................... 15 
4.0 
Treatment Plan ............................................................................................................. 16 
5.0 
Background Drug Information ....................................................................................... 18 
5.1    
Study Medication ................................................................................................... 18 
5.1.1   
Ibrutinib .............................................................................................................. 18 
5.1.2   
Formulation/Packaging/Storage/Disposal .......................................................... 18 
5.1.3   Dose and Administration ....................................................................................... 18 


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5.1.4   Overdose .............................................................................................................. 18 
6.0  
Concurrent Medications/Procedures ............................................................................. 19 
6.1 
Permitted Concomitant Medications .......................................................................... 19 
6.2 
Medications to be Used with Caution ........................................................................ 20 
6.2.1 
CYP3A- Inhibitors/Inducers ................................................................................ 20 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, 
please refer to the current version of the IB. ..................................................................... 20 
6.2.2 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ........... 20 
6.2.3 
QT Prolonging Agents ........................................................................................ 20 
6.2.4 
Antiplatelet Agents and Anticoagulants .............................................................. 21 
6.3 
Prohibited Concomitant Medications ......................................................................... 21 
6.4 
Guidelines for Ibrutinib Management with Surgeries or Procedure ............................ 21 
6.4.1     Minor Surgical Procedures .................................................................................. 21 
6.4.2     Major Surgical Procedures .................................................................................. 22 
6.4.3     Emergency Procedures ....................................................................................... 22 
7.0 
Study Evaluations ......................................................................................................... 22 
7.1  
Disease monitoring ................................................................................................... 22 
7.2        Safety Monitoring .................................................................................................... 24 
7.3 
Outside Physician Participation During Treatment .................................................... 24 
7.4    Optional lab studies .................................................................................................... 25 
7.4.1  
Rationale ........................................................................................................... 25 
7.4.2  
Tests and Schedule ........................................................................................... 26 
8.0 
Criteria for Removal from the Study .............................................................................. 26 
9.0 
Statistical Considerations ............................................................................................. 26 
10.0  
Adverse Event Reporting .......................................................................................... 28 
10.1 
Definitions ................................................................................................................. 29 
10.1.1 
Adverse Events .................................................................................................. 29 
10.1.2 
Severity Criteria (Grade 1-5) .............................................................................. 30 
10.1.3 
Causality (Attribution) ......................................................................................... 30 
10.2 
Unexpected Adverse Events ..................................................................................... 30 
10.3 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ........................................................................................................................ 31 
10.3.1 
Assessment of Adverse Events.......................................................................... 31 


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10.3.2 
Adverse Event Reporting Period ........................................................................ 31 
10.3.3 
Pregnancy ......................................................................................................... 32 
10.3.4 
Other Malignancies ............................................................................................ 32 
10.3.5     Adverse Events of Special Interest (AESI) ........................................................ 32 
10.3.6 
Serious Adverse Events (SAE) .......................................................................... 33 
10.3.7 
  Investigator Communications with Pharmacyclics, Inc. .................................... 34 
11.0 
Study Administration and Principal Investigator Obligations ......................................... 34 
12.0 
References ................................................................................................................... 34 
 
 
 


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Protocol Body 
1.0   Objectives 
 
1.1 
Primary objective 
 
 
1.1.1  Determine the efficacy of the use of Ibrutinib maintenance after autologous stem cell 
transplantation (SCT) in double-hit lymphoma, defined by the 2-year disease-free 
survival (DFS) rate.  
1.2 
Secondary objectives 
 
 
1.2.1   Estimate safety and toxicity, DFS, and overall survival (OS). 
 
 
1.2.2 Estimate efficacy and DFS at 3, 6, 9, 12 months and every 6 months thereafter for 3 
years. 
 
1.3  
Tertiary objectives 
 
1.3.1 Exploratory Correlative studies. 
2.0   Background 
 
2.1  
Oncogenes involved in DHL 
 
Double-hit lymphoma (DHL) has been defined as a B-cell lymphoma with MYC/8q24 
rearrangement in combination with a translocation involving another gene, such as BCL2, 
BCL3 or BCL6.
1-3 The most common form of DHL has translocations involving MYC and BCL2, 
also known as MYC/BCL2 DHL. BCL2, located at 18q21, encodes an anti-apoptotic 
protein. The t(14;18)(q32;q21) juxtaposes BCL2 with the IGH gene enhancer at 14q32, 
resulting in BCL2 overexpression. BCL2 also has a role in physiological DNA repair. It is 
hypothesized that the coexistence of MYC and BCL2 translocations in MYC/BCL2 DHL results 
in markedly increased cell proliferation and decreased apoptosis, resulting in rapid tumor 
growth.  
 
2.2  
Morphology and Immunophenotyping 
 
MYC/BCL2 DHL was once thought to be uncommon, representing, 1% of all lymphomas and 
approximately 4% of high-grade B-cell lymphomas reported in the older literature.
1,-6 More 
recent studies in which MYC and BCL2 were tested routinely, however, have shown that 
MYC/BCL2 DHL is more common than had been appreciated with a frequency that is 
approximately 10%.
7 The historical underestimation of its frequency was likely due to at least 2 
reasons. The first is that traditionally cases of aggressive e B-cell lymphoma have not been 
routinely tested by conventional cytogenetics or FISH. Secondly, translocations can be difficult 
to recognize using conventional karyotyping methods in a subset of tumors.
8 


2014-0096 
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Approximately 80% to 85% of cases of MYC/BCL2 DHL arise in patients de novo, whereas 
15% to 20% of cases are thought to have progressed from follicular lymphoma. Most cases of 
MYC/BCL2 DHL morphologically resemble diffuse large b-cell lymphoma (DLBCL) or B cell 
lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma 
(BCLU).
1-3 Translocations can be difficult to recognize using conventional karyotyping methods 
in a subset of tumors. Traditionally, cases of aggressive B-cell lymphoma have not been 
routinely tested by conventional cytogenetic or fluorescence in situ hybridization (FISH). 
Pedersen et al
7 studied 157 patients with DLBCL or BCLU. All 157 cases were analyzed by 
using FISH with MYC and BCL2 break-apart probes and 11% of the cohort was MYC/BCL2 
DHL. This subset represented 7% of de novo lymphomas and 21% of transformed lymphomas. 
These tumors are of B-cell lineage and have a germinal center B-cell immunophenotype 
(CD10, BCL6, MUM1/IRF4) with a high proliferation rate.  
 
2.3  
Clinical Features 
 
In recent years, a number of small series of MYC/BCL2 DHL have been published.
1-3 DHL 
occurs mainly in older patients and slightly more often in men. The median age at diagnosis 
has ranged from 51 to 65 years, which is older than patients with BL (fourth decade), but 
slightly younger than patients with DLBCL (seventh decade). In another study of 97 children 
with aggressive B-cell lymphomas, no cases of MYC/BCL2 DHL were identified.
9 Patients with 
double hit lymphoma have extremely poor adverse prognostic features. Most patients with 
MYC/BCL2 DHL present with advanced stage disease (Ann Arbor III/IV). Extranodal sites of 
involvement are frequent, with the bone marrow and central nervous system being involved 
most commonly. Virtually any extranodal site can be involved. An elevated serum lactate 
dehydrogenase level is very common in patients with MYC/BCL2 DHL. Most patients have a 
high-intermediate or high International Prognostic Index (IPI). Snuderl et al
10 compared 
MYC/BCL2 DHL patients with IPI-matched DLBCL patients and found that the former group 
had a higher median LDH level at presentation (727 vs. 366 U/L) and higher frequency of bone 
marrow involvement (59% vs. 23%).  
No standardized treatment approach is established. As shown in Table 1, patients with 
MYC/BCL2 DHL have been treated with different regimens, including traditional chemotherapy 
regimens and more aggressive chemotherapy.  The median overall survival of newly 
diagnosed MYC/BCL2 DHL patients is very poor, ranging from 2 months to 1.5 years, 
regardless of the therapeutic regimen employed regimens with or without stem cell transplant. 
The most common traditional regimens that have been used are R-CHOP (rituximab, 
cyclophosphamide, daunorubicin, vincristine, prednisone) or CHOP. More aggressive 
chemotherapy regimens used include Hyper-CVAD (hyperfractionated cyclophosphamide, 
vincristine, doxorubicin, and dexamethasone), R-Hyper-CVAD, and R-EPOCH (Table 1).  
 
 
 
 
 


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Table 1 
 
 
 No. of DH/total 
 
 
 
 
 
                   Overall response 
   Study 
 
  Study size (%) 
Treatment regimen*  
 
 
 
rate, n/N(%)†         Median Survival, y 
Bertrand et al40 2007 10/17 (59) 
NA 
5/10‡ (50) 
< 1§ 
Johnson et al15 2009 54/54 (100) 
RCHOP (11/54);HDC+/- SCTl (6/54); CHOP (23/54); P (14/54) 
NA 
HD, 0.26; RCHOP, 1.40; 
CHOP-like, 0.42; P 0.07 
Kanungo et al13 2006 14/14 (100) 
CT-NOS (11); R¶ (1); CT and BMT (1); CT, BMT, and RT (1) 
NA 
< 1§ 
Le Gouill et al10 2007 
16/16 (100) 
CEEP/COPADM + Auto-SCT/BEAM (1); CHOP/IVAM (1); COPADM/CYVE (3); 
12/16 (75) 
0.42 
                                                                             COPADM (1); COPADM + Auto-SCT/BEAM (1); COPADM + Allo-SCT/Bu/Cy (1) 
                                                                             CEEP/DHAP + Auto-SCT/BEAM (1); RCHOP (4); CHOP (1); Steroids# (1); 
                                                                             R-CEEP Allo-SCT/TBI/Cy (1) 
Macpherson et al112 
1999
15/39 (38) 
CHOP-variant or cyclophosphamide + MTX (6); HDC +/- SCT (3); P (4) 
NA 
0.21 
Niitsu et al12 2009 
19/19 (100) 
CyclOBEAP (6); CHOP + HD MTX (3); CHOP (4); RCHOP (3), CyclOBEAP + R (3) 
17/19 (89) 
1.50 
Snuderl et al14 2010
20/20 (100)
R-ICE + MTX/ASCT (1); CHOP (1); RCHOP (3); RCHOP + MTX (6); RCHOP + MTX 
10/20** (50)
0.38
                                                                  + ASCT (1); R-EPOCH + MTX (3); CODOX- + MTX/R-IVAC (3); P (1); NK(1) 
   Tomita et al11 2009        27/27 (100)    CHOP or CODOX-M/IVAC or HyperCVAD (+ R, n = 14; -R, n = 8)†† 
                         6/23 (26)††           
(Adopted from Aukema et al. Blood 2001;117:2319-2331). 
 
2.4  
Rationale for Stem Cell Transplantation (SCT) 
 
In a recent multicenter respective analysis,
11 newly diagnosed DHL patients were treated with 
either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-
CODOX-M/IVAC, R-ICE. One hundred six patients were analyzed. Fourteen (13%) were 
consolidated with SCT (n=1 allogeneic and n=13 autologous SCT). While the induction 
regimen did not impact survival rates in patients not receiving SCT, SCT in first remission was 
associated with improved overall survival (P = 0.02), and progression-free survival (P = 0.006) 
compared with induction alone.  
 
2.5  
Targeting B-cell receptor 
 
The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an 
increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in 
tumorigenesis.
12,13  
 
Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by 
microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations 
in intracellular components of the BCR pathway. Chronic lymphocytic leukemia (CLL) has been 
recognized for decades as a malignancy of auto-reactive B-cells and its clinical course is in 
part determined by the differential response of the malignant cells to BCR activation. Initial 
antigen selection during transformation or continued antigenic drive appears to play a role in 
additional B-cell malignancies, including mantle cell lymphoma (MCL) and follicular lymphoma 
(FL), resulting in activation of the NF- kB pathway.
12,13  
 
The mechanism of signaling in DHL has not been studied. The hallmark of BL is a translocation 
of MYC to the Ig heavy chain locus. However, MYC has strong pro-apoptotic effects and 
requires activation of pro-survival signaling through the PI3K pathway. Because of the 
MYC/BCL2 translocation in DHL, it is plausible that activation of BCR signaling occurs through 
a combination of extrinsic signaling, by antigenic drive (as in FL with BCL2), and intrinsic 


2014-0096 
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signaling, due to acquired mutations (as in BL).
12,13  A prominent example of this process is 
observed in a subset of activated B-cell (ABC) DLBCLs. 
 
Targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm 
for many B-cell malignancies. Bruton’s tyrosine kinase (BTK), an essential component of B-
cell–receptor signaling, mediates interactions with the tumor microenvironment. In the first 
clinical trial (see Appendix C., Package Insert) reported with BTK-inhibitor ibrutinib at 560 mg 
po/day, an overall response of 54% across different B-cell malignancies was reported, 7/9 for 
MCL,11/16 for CLL, 6/16 for FL (later updated with response in 11/16 patients), and 2/7 for 
DLBCL.
14 Another study for DLBCL patients showed responses for ABC but not GCB subtypes 
in agreement with the preclinical data on the importance of BTK signaling preferentially in ABC 
DLBCL (two partial responses (PR) and one CR out of 10 patients).  More recently, overall 
response rate (ORR) of 71% for treatment naïve CLL patients, 67% for relapsed or refractory 
patients, and 50% for high risk patients has been reported.
15 A recent report from a phase II 
study in relapsed MCL (n = 111, 48 previously bortezomib treated) showed ORR of 68% and 
CR of 21%; after a median of 15.3 months follow up the estimated progression-free survival 
was 13.9 months.
16  
 
2.6  
Rationale for maintenance ibrutinib after stem cell transplantation in DHL 
 
Despite considerable heterogeneity in biology and clinical course, many mature B-cell 
malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Relapse 
remains the major cause of failure after hematopoietic transplantation. Maintenance targeted 
therapy has been emerging as an important strategy to treat microscopic resistant clones. The 
safety profile of BTK-inhibitor ibrutinib is encouraging. Specifically, grade 3 or higher 
hematologic events were infrequent suggesting that extended treatment of the drug may be 
well tolerated after stem cell transplantation.  
 
2.7  
Correlative studies 
 
Various mechanisms of clinical non-responses have been found to Ibrutinib therapy.
13,18 
Mutations within the CD79A, CD79 B part of the BCR that increase the response to antigenic 
drive and activating mutations (CARD11, caspase recruitment domain-containing protein 11) in 
downstream signal transduction components may confer antigen independent pro-survival 
signaling. Blood levels of BCR-driven chemokines CCL 3 and CCL 4 (T-cell-recruiting 
chemokines) are biomarkers of initial response in CLL. MYD88 (myeloid differentiation primary 
response protein 88) mutations has been shown to induce resistance to ibrutinib in ABC-
DLBCL. Recent studies in MCL found that mutations in TRAF2 or BIRC3 are associated with 
insensitivity to BCR inhibitors.
17 We propose to study these pathways in our study.  
 
Micro-RNAs (miRNAs) are central regulators of gene expression, and their relevance in cancer 
is now well established.
19 It has been shown recently that MYC plays a key role in determining 
the miRNA expression signature of DLBCL by negatively regulating the expression of a host of 
miRNAs and to transcriptionally activate the miR-17-92 cluster.
20 Studying mirRNA in DHL and 
the impact of ibrutinib on its expression is a correlative study of interest in this study.  
 
 
 


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2.8  
Ibrutinib  
2.8.1  Background 
 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream BCR signaling pathways and thus 
prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and selected members of the 
kinase family with 10-fold specificity compared with non-BTK kinases.  Ibrutinib (IMBRUVICA 
™) is approved  by the U.S. Food and Drug Administration (FDA) for the treatment of patients 
with CLL (at a dose of 420 mg po daily),  patients with CLL 17p deletion, MCL (at a dose of 560 
mg po daily) who have received at least one prior therapy, and Waldenstrom’s 
Macroglobulemia (WM).  Ibrutinib is currently under investigation in various indications.   
 
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the 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.
21  
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.
22  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.
23  
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 postdose 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. 
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to the 
latest version of the ibrutinib Investigator's Brochure. 
2.8.2  Summary of Nonclinical Data 
 
For the most comprehensive nonclinical information regarding ibrutinib, refer to the current 
version of the Investigator's Brochure.  


2014-0096 
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2.8.3  Pharmacology  
 
Ibrutinib was designed as a selective and covalent inhibitor of the Btk.
24 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.
25 
 
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 (Herman 2011)   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 progression26 
 
For more detailed and comprehensive information regarding nonclinical pharmacology, refer to 
the current Investigator’s Brochure. 
2.8.4   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 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 patients administered the dose of 560 mg daily, respectively.     
2.8.5  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. 


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2.8.6  Summary of Clinical Data 
 
For the most comprehensive clinical information regarding ibrutinib, refer to the current version 
of the Investigator's Brochure.  
2.8.7  Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging 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.  Taking into account the approximate 
doubling in mean systemic exposure when dosed with food and the favorable safety profile, 
ibrutinib can be dosed with or without food. Ibrutinib is extensively metabolized primarily by 
cytochrome P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not 
considered clinically relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 
2-fold of first dose exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is 
not altered in patients with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal 
impairment or patients on dialysis have not been studied. Following single dose administration, 
the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), 
moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared 
to subjects with normal liver function.  A higher proportion of Grade 3 or higher adverse 
reactions were reported in patients with B-cell malignancies (CLL, MCL and WM) with mild 
hepatic impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for 
hepatic dysfunction compared to patients with normal hepatic function.  
2.8.8  Ibrutinib safety profile 
 
A brief summary of safety data from monotherapy therapy studies is provided in below. For 
more comprehensive safety information please refer to the current version of the IB. Additional 
safety information may be available for approved indications in regional prescribing labels 
where the study is conducted (eg, USPI, SmPC).  
For monotherapy studies: 
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.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071): 
 
 


2014-0096 
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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 Investigator’s Brochure. 
2.8.8.1 
Treatment Discontinuations 
As of 6 April 2013, 71/636 subjects discontinued treatment due to an adverse event, across the 
monotherapy and combination therapy ibrutinib studies (excluding Study PCYC-1103-CA); 62 
subjects receiving monotherapy population and 9 subjects receiving combination therapy.  The 
most frequently reported adverse events that led to treatment discontinuations were 
pneumonia (13 subjects), respiratory failure (4 subjects), and cardiac arrest and Richter’s 
Syndrome (3 subjects each).   
2.8.8.2 
Bleeding-related events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, 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. 
Subjects with congenital bleeding diathesis have not been studied. See Section 6.2.4 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.4 for guidance on ibrutinib management with surgeries or procedures.   
Lymphocytosis and Leukostasis 
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. For subject and 
ibrutinib management guidance, refer to Section 4.0. 
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 CLL/ small lymphocytic lymphoma 


2014-0096 
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(SLL) 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 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. 
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). 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 
patients treated with ibrutinib. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) 
were reported in subjects treated with ibrutinib. 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, 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 6.2.4). 
Second Primary Malignancies 
Second primary malignancies, most frequently skin cancers, have occurred in subjects treated 
with ibrutinib. Second primary malignancies including non-skin carcinomas have occurred in 
patients treated with ibrutinib. The most frequent second primary malignancy was non-
melanoma skin cancer.  
Tumor Lysis Syndrome 
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 


2014-0096 
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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 4.0). 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to 
moderate in severity.  
Interstitial lung disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated wih ibrutinib. 
Randomized, controlled Phase 3 studies did not show an increased incidence rate of ILD in 
subjects treated with ibrutinib as compared to subjects treated with active control. Subjects 
should be monitored and evaluated for symptoms (e.g., dyspnea, cough or pyrexia) and treated 
symptomatically, including interruption of the suspected agent as appropriate. 
For subject and ibrutinib management guidance, refer to Section 4.0. 
 
 


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3.0 
Patient Eligibility 
 
3.1   
Inclusion Criteria 
3.1.1   Patients with newly diagnosed double hit in first complete remission, anytime during the 
first 3 months after chemoimmunotherapy followed by autologous stem cell 
transplantation if there was no evidence of progression.  
3.1.2  Double hit lymphoma is defined as B-cell lymphoma with genetic abnormalities 
involving A) and in addition, B) and/or C):  
 
A)  C-MYC arrangement or amplification by FISH study. 
B)  BCL2 rearrangement or amplification by FISH study.  
C)  BCL6 rearrangement or amplification by FISH study. 
 
3.1.3   ANC >/= 1,000, platelets >/= 75,000. 
 
3.1.4   AST and/or ALT < 3 times the ULN. 
 
3.1.5   Creatinine clearance > 30 ml/min (Cockcroft-Gault formula using ideal body weight). 
 
3.1.6  Male or female age >/= 18 years. 
 
3.1.7 ECOG performance status </= 2. 
 
3.1.8 Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules without difficulty. 
 
3.1.9 Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information. 
 
3.1.10 Patient should preferably have received a pre-transplant conditioning with rituximab and 
Carmustine/Etoposide/Cytarabine/Melphalan/Rituxan (BEAM/R) . Other regimens which 
are similar may be accepted at the discretion of the PI.  
 
3.2  
Exclusion Criteria 
 
3.2.1 Prior chemotherapy within 3 weeks, nitrosoureas (carmustine) within 6 weeks, 
therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates 
within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of 
first dose of study drug. 
 
3.2.2 Relapsed within three months post-transplant. 
 
3.2.3 History of other malignancies within the past year except for treated basal cell or 
squamous cell skin cancer or in situ cervical cancer. 
 
3.2.4 Known CNS lymphoma. 
 


2014-0096 
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3.2.5 Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 (moderate) or 4 (severe) cardiac disease as defined by the 
New York Heart Association Functional Classification. 
 
3.2.6 Requires treatment with a strong cytochrome P450 (CYP)3A inhibitor (i.e. Voriconazole, 
posaconazole, itraconazole, clarithromycin, etc.) or inducer (carbamazepine, rifampin, 
phenytoin, etc.). 
 
3.2.7 AST and/or ALT >/= 3 times the ULN. 
 
3.2.8 Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel or symptomatic ulcerative colitis, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
 
3.2.9 Known history of human immunodeficiency virus or active infection with hepatitis C 
virus or hepatitis B virus or any uncontrolled active systemic infection. 
 
3.2.10 Positive pregnancy test in women of childbearing potential. 
 
3.2.11 Lactating or pregnant or will not agree to use contraception during the study and for 30 
days after the last dose of study drug if sexually active and able to bear children. 
 
3.2.12  Concomitant use of warfarin or other Vitamin K antagonists. 
4.0 
Treatment Plan 
 
4.1    Ibrutinib will be started at a daily dose of 560 mg po daily.   
 
4.2    Patients will continue on Ibrutinib until relapse, or AE not managed by dose adjustment, 
or upon completion of 3 years on ibrutinib. Dose will be adjusted should cytopenia or 
other non-hematologic toxicity occur (Sections 4.4 and 4.5). 
 
4.3  
For patients requiring surgery, ibrutinib should be held 3 to 7 days prior to surgery 
(depending on surgery type and bleeding risk) and hold for 7 days post-surgery. 
 
4.4 
Parameters to hold/interrupt ibrutinib: 
• 
Grade >/= 3 neutropenia with fever. 
• 
Grade 4 neutropenia lasting > 7 days (despite use of GCSF). 
• 
Grade 3 or 4 platelet counts < 50,000/microL in presence of significant bleeding. In 
subjects with baseline thrombocytopenia, a platelet decrease of 50 to 75% in 
presence of significant bleeding. 
• 
Grade 4 platelets < 25,000/microL or, in subjects with baseline thrombocytopenia, 
decrease of > 75% from baseline or < 20,000/microL, whichever is higher. 
• 
Any Grade >/= 3 non-hematologic toxicity. 
 
 
 


2014-0096 
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4.5     Toxicity Management 
Toxicity 
occurrence 
Action 
Toxicity not related to 
study drug 
Toxicity related to 
study drug 
First 
Hold drug until resolution to 
grade I or to baseline.  
Restart at original dose Restart at 420 
mg/day 
Second 
Hold drug until resolution to 
grade I or to baseline.  
Restart at 420 mg/day 
Restart at 280 
mg/day 
Third 
Hold drug until resolution to 
grade I or to baseline.  
Restart at 280 mg/day 
Restart at 
140 
mg/day 
Fourth 
Hold drug until resolution to 
grade I or to baseline.  
Stop medication, do not 
re-challenge 
Stop 
medication, do 
not re-
challenge 
If the dose of ibrutinib/placebo is reduced, at the investigator’s discretion, the dose of ibrutinib 
may be re-escalated after 2 cycles of a dose reduction in the absence of a recurrence of the 
toxicity that led to the reduction. Dose changes must be recorded in the Dose Administration 
eCRF.  
Leukocytosis/Leukostasis 
A high number of circulating malignant cells (>400000/mcL) may confer increased risk of 
leukostasis; these subjects should be closely monitored. Administer supportive care such as 
hydration and/or leukophoresis as indicated. Ibrutinib may be temporarily held, and investigator 
should be contacted. 
Dose Modification for Hepatic Impaired Subjects 
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 a level of 280 mg daily (two capsules). 
For subjects who develop moderate liver impairment while on study (Child-Pugh class B), the 
recommended dose reduction is to a level of 140 mg daily (one capsule). Subjects who 
develop severe hepatic impairment (Child-Pugh class C) must hold study drug until resolved to 
moderate impairment (Child-Pugh class B) or better. Monitor subjects for signs of toxicity and 
follow dose modification guidance as needed (Section 4.5). 


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5.0 
Background Drug Information 
 
5.1    Study Medication 
5.1.1   Ibrutinib  
5.1.2   Formulation/Packaging/Storage/Disposal 
 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  All 
formulation excipients are compendial and are commonly used in oral formulations.  Refer to 
the ibrutinib Investigator's Brochure for a list of excipients.  
 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All 
study drug will be dispensed in child-resistant packaging.   
Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
Any unused or expired drug will be discarded following the MD Anderson Investigational 
Pharmacy’s standard operating procedures. 
5.1.3   Dose and Administration  
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily. The capsules are to 
be taken around the same time each day with 8 ounces (approximately 240 mL) of water.  The 
capsules should be swallowed intact and patients should not attempt to open capsules or 
dissolve them in water. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville 
oranges should be avoided for the duration of the study. 
 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same 
day with a return to the normal schedule the following day.  The patient should not take extra 
capsules to make up the missed dose. 
 
The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically 
on an outpatient basis.  Ibrutinib will be dispensed to patients in bottles at each visit.  Unused 
ibrutinib dispensed during previous visits must be returned to the site and drug accountability 
records updated at each visit.  Returned capsules must not be redispensed to anyone. 
5.1.4   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.  


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There is no specific experience in the management of ibrutinib overdose in patients. 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/day). Healthy subjects were exposed up to single dose of 1680 
mg. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and 
ALT) after a dose of 1680 mg. Subjects who ingested more than the recommended dosage 
should be closely monitored and given appropriate supportive treatment. 
Refer to Section 10.0 for further information regarding AE reporting.  
5.1.5   Pharmacokinetics 
 
Distribution: ~10,000 L 
 
Bioavailability: Administration with food increased exposure ~2-fold (compared to overnight 
fasting) 
 
Protein binding: ~97% 
Metabolism: Hepatic via CYP3A (major) and CYP2D6 (minor) to active metabolite PCI-45227 
Half-life elimination: 4-6 hours 
Time to peak: 1-2 hours 
Excretion: Feces (80%; ~1% as unchanged drug); urine (<10%, as metabolites) 
6.0  
Concurrent Medications/Procedures 
 
6.1 
Permitted Concomitant Medications 
 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, 
etc.) are permitted.  Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood 
cell growth factors (erythropoietin) is permitted per institutional policy.  Transfusions may be 
given in accordance with institutional policy.  
Short courses (</=14 days) of steroid treatment for non-cancer related medical reasons (e.g., 
joint inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses 
that do not exceed 100 mg per day of prednisone or equivalent are permitted. 
After consultation with the investigator the following may be considered: localized hormonal or 
bone sparing treatment for non-B-cell malignancies, and localized radiotherapy for medical 
conditions other than the underlying B-cell malignancies.   
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 
100 mg per day of prednisone or equivalent. 
As stated above, patients treated on this protocol may require supportive care treatment 
(concomitant medications).  These medications are considered standard of care and have no 
scientific contribution to the protocol; therefore no data will be captured on various medications 
needed or their side effects.  


2014-0096 
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6.2 
Medications to be Used with Caution 
6.2.1 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 Section 5.1.3) 
 
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 3.  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. 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib 
exposure, please refer to the current version of the IB. 
6.2.2 Drugs That May Have Their Plasma Concentrations 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 g/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 
6.2.3 QT Prolonging Agents 
 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered.  


2014-0096 
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6.2.4 Antiplatelet Agents and Anticoagulants 
 
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 (see Section 6.4). 
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment.  If therapeutic anticoagulation 
is clinically indicated, treatment with ibrutinib should be held and 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. 
 
6.3 
Prohibited Concomitant Medications 
 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are 
prohibited while the subject is receiving ibrutinib treatment.   
Corticosteroids for the treatment of the underlying disease is prohibited.  Corticosteroids for the 
treatment of non-cancer related reasons for longer than 14 days and/or at doses > 100mg of 
prednisone or its equivalent are prohibited.   
6.4 
Guidelines for Ibrutinib Management with Surgeries or Procedure 
 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for patients who 
require surgical intervention or an invasive procedure while receiving ibrutinib:   
6.4.1     Minor Surgical Procedures 
 
For 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.   
 
 


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6.4.2     Major Surgical Procedures 
 
For any 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.   
6.4.3     Emergency Procedures 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, or for at least 7 days after the urgent surgical procedure, whichever is 
longer. 
7.0 
Study Evaluations 
 
7.1  
Disease monitoring  
7.1.1    Patients will be assessed at 3, 6, 9, and 12 months after the first dose of ibrutinib, then 
every 6 months for 3 years.  After 3 years, patients will be followed according to MD 
Anderson’s Department of Stem Cell Transplant and Cellular Therapy standard of care 
guidelines.  
 
 


2014-0096 
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Table of Evaluations 
 
Protocol 2014-0096 
Within 4 weeks of the 1st dose 
Weekly for the first 4 weeks after 
1st dose 
Then every 2 weeks for 4 weeks 
after 1st dose 
Monthly1 
1 month (+/-5 days) after 1st 
dose 
2 months (+/-5 days) after 1st 
dose 
3 months (+/-5 days) after 1st 
dose 
6 months (+/-15 days) after 1st 
dose 
9 months (+/-15 days) after 1st 
dose 
12 months (+/-15 days) after 1st 
dose 
Every 6 months (+/-15 days) for 
3 years  after 1st dose6 
Yearly post-transplant while 
taking ibrutinib  
History and physical 
exam, vital signs, 
performance status 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
CBC, creatinine, liver 
function tests 
 
X 
X 
X1 
 
 
 
 
 
 
 
 
Peripheral blood CD4, 
CD8, immunodeficiency 
panel2 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Immunoglobulin levels 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Bone marrow 
aspiration/biopsy 
(unilateral) 
 
 
 
 
X3 
 
X 
X 
X 
X 
X 
 
CT scans (neck, 
abdomen, pelvis) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
PET4 
 
 
 
 
 
 
 
 
 
 
 
X 
Research Tests (Optional) 
X5 
 
 
 
X5 
 
X5 
X5 
 
 
 
 
 
1   Monthly after 1st study drug dose, if no need for dose reductions or holding of medication. Labs 
may be checked more often at physician’s discretion. 
2 Only repeat immunodeficiency panel in patients with recurrent infections. 
3  No bone marrow aspiration/biopsy at Month 1 after the 1st dose if negative pre-transplant. 
4   PET only if positive at transplant, and do not repeat after it becomes negative. 
5  See protocol Section 7.4 for details.  
6 After 3 years, patients will be followed according to MD Anderson’s Department of Stem Cell Transplant 
and Cellular Therapy standard of care guidelines.  
 
 


2014-0096 
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7.1.2   The International Working Group response criteria will be used. 
 
 
Response 
 
Definition 
 
Nodal  Masses 
 
Spleen, Liver 
 
Bone Marrow 
CR 
Disappearance of all evidence   of 
disease 
 
(a) FDG-avid or PET positive prior to 
therapy; mass of any size permitted 
if PET negative                                
(b) Variably FDG-avid or PET 
negative; regression to normal size 
on CT 
Not palpable, nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of measurable disease 
and no new sites 
> 50% decrease in SPD of up to 6 
largest dominant masses; no 
increase in size of other nodes              
(a) FDG-avid or PET positive prior to 
therapy; one or more PET positive at 
previously involved site                          
(b) Variably FDG-avid or PET 
negative; regression on CT 
> 50% decrease in      
SPD of nodules (for   
single nodule in  
greatest transverse  
diameter); no  increase 
in size of  liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
SD 
Failure to attain CR/PR or PD 
(a) FDG-avid or PET positive prior to 
therapy; PET                                          
positive at prior sites of disease and 
no new sites on CT or PET                    
(b) Variably FDG-avid or PET 
negative; no change in                          
size of previous lesions on CT 
 
 
Relapsed disease 
or PD 
Any new lesion or increase by 
>50% of previously involved sites 
from nadir                       
Appearance of a new lesion(s) >1.5 
cm in any axis, >50% increase in 
SPD of more than one node, or 
>50% increase in longest diameter of 
a previously identified node > 1 cm in 
short axis. 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy 
>50% increase from 
nadir in the SPD of any 
previous lesions 
New or recurrent 
involvement 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial 
remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease. 
 
7.2        Safety Monitoring  
 
The following labs may be done at the designated time points by their home physician and the 
results sent to the MDACC clinical research team.  The PI/treating physician will review these 
labs, determine clinical significance, and sign/date the results.  Concomitant medication data 
will not be collected. 
 
7.2.1       Complete blood counts, creatinine, LFTs as follows: 
 
Weekly for the first four weeks of therapy, then 
 
Every 2 weeks for 4 weeks, then 
 
Monthly thereafter (If no need for dose reductions or holding of medication) 
 
7.2.2 Patients may have labs checked more frequently at the discretion of the physician. 
 
7.3 
Outside Physician Participation During Treatment 
 
MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. 
 


2014-0096 
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This will be documented in the patient record.  Protocol-specific treatment decisions must be 
made by the MDACC physician.   
A letter to the local physician outlining the patient's participation in a clinical trial will request 
local physician agreement to supervise the patient's care (Appendix G.). 
Protocol required evaluations outside MDACC will be documented by fax or e-mail.  Fax and/or 
e-mail will be dated and signed by the MDACC physician, indicating that they have reviewed it. 
Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in the 
patient record. 
A copy of the informed consent, protocol abstract, and Table of Assessments (Appendix D.) 
during treatment will be provided to the local physician. 
Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hospitalizations. 
The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
Patients will return to MDACC every 3, 6, 9, and 12 months, then every 6 months for 3 years 
after the first dose of ibrutinib, then yearly as long as they are receiving ibrutinib.  
7.4    Optional lab studies 
7.4.1  Rationale 
 
Please see Section 2.7. 
 
 


2014-0096 
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7.4.2  Tests and Schedule 
  Initial                  Pre-Ibrutinib                            Post-Ibrutinib 
 
 
 
 
 
 
 
 
8.0 
Criteria for Removal from the Study 
 
8.1   
Disease progression. 
 
8.2   
Intolerable side effects. 
 
8.3   
Unable to follow study directions. 
 
8.4   
Withdrawal of consent. 
 
8.5 
Completion of 3 years on study drug. 
9.0 
Statistical Considerations 
 
We expect to accrue a total of 30 autologous stem cell transplant patients. The primary 
endpoint is to estimate the disease-free survival rate at 2 years. With 30 patients, we have 80% 
power to detect an improvement in this rate from 50% associated with standard of care to 75%, 
assuming a 5% Type I error rate using an exact test for a single proportion (calculated in 
nQuery v7.0). The primary endpoint will be estimated using a 95% confidence interval, and 
drop-outs will be counted as non-responders. A toxicity monitoring rule is provided below to 
ensure the study will stop early if there is a high chance of a toxicity rate higher than 30%. A 
futility monitoring rule is not included since it is unlikely that this maintenance therapy will 
worsen the 2-year disease-free survival rate compared to standard of care, i.e. no 
maintenance. 
 
The monitoring rule will be assessed by the study team with assistance as necessary from the 
Department of Biostatistics at MD Anderson Cancer Center.  
Before 1st dose         D30 (+/-5)      D100 (+/-5)      D180 (+/-15) 
Tumor-based studies (paraffin-embedded or frozen tissue) 
Mutation analysis:  MYD88, TRAF2, BIRC3 
FISH:  MYC, BCL2, BCL6 
Protein:  MYC, BCL2, BCL6, CD38, CD44, CD79A, CD79B, CARD1, PD1, PD1L 
miRNA:  16-1, 17-92 cluster, 21, 155, 29, 26a, 196b, 494 
Blood-based studies:  
Serum: 
   Cytokines:  CCL2 (MCP1), CCL4 (MIP-1), CXCL13, IL-10, IL-6, TGF-b, TNF-a 
   miRNA:  16-1, 17-92 cluster, 21, 155, 29, 26a, 196b, 494 
Buffy coat:  Tregs, T cell subsets, Th1/Th2, NK subsets 


2014-0096 
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Toxicity monitoring rule: If at any time there is a high probability of observing more than a 30% 
toxicity rate, the study will be stopped. Toxicity includes any grade IV toxicity requiring a drug 
hold of more than 2 weeks within the first four cycles that does not resolve with dose reduction. 
Bayesian sequential monitoring
29 will be employed to perform interim safety monitoring 
targeting a toxicity rate of not more than 30%. Patients will be monitored in cohorts of 1. The 
study will be stopped if  
 
Pr [ prob(toxicity) > 0.30 | data] > 0.97 
 
That is, if we determine that there is a greater than 97% chance that the toxicity rate is greater 
than 30%, the study will be stopped. We assume a beta (0.6, 1.4) prior distribution for the 
experimental toxicity rate, which has a mean of 0.3 corresponding to the 30% target toxicity 
rate. We assume a beta (300, 700) prior distribution for the standard treatment toxicity rate.  
Stopping boundaries corresponding to this probability criterion are to terminate accrual if  
 
Table 2 
If there are this many 
(or more) patients with 
Toxicity 
 
Total number of  
patients evaluated   
Never stop with this 
many patients 
 
 
1-3 
4 
4 
5-6 
5-6 
6-9 
7-9 
7-11 
10-11 
8-13 
12-13 
9-16 
14-16 
10-18 
17-18 
11-21 
19-21 
12-23 
22-23 
13-26 
24-26 
14-28 
27-28 
15-29 
29 
Always stop at 30 
patients 
 
30 
 


2014-0096 
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Patients must complete at least two months of treatment or have toxicity to be included in the 
rule. Patients who complete at least two months but drop out without experiencing toxicity will 
be included but not counted as toxicities.  
 
This stopping rule was chosen to assure that the probability of early stopping would be 
approximately 7% if the true rate of toxicity was no more than 30%. The operating 
characteristics of this rule are shown below. The stopping boundaries and operating 
characteristics were calculated in the Department of Biostatistics using the software Multc Lean 
Desktop v1.2.0. 
 
Table 3. Operating Characteristics for Toxicity Stopping Rule  
If the true 
toxicity 
rate is… 
Early Stopping 
Probability 
Achieved Sample Size 
25th, 50th, 75th percentiles 
0.1 
0.0002 
30 
30 
30 
0.2 
0.0070 
30 
30 
30 
0.3 
0.0709 
30 
30 
30 
0.4 
0.3114 
21 
30 
30 
0.5 
0.6875 
9 
18 
30 
0.6 
0.9338 
6 
9 
16 
 
 
Secondary and tertiary objectives 
For secondary objectives, we will estimate response, safety, and toxicity at 3, 6, 9, and 12 
months after treatment initiation and then every 6 months x 3 years with a 95% confidence 
interval.  We may also estimate specific response types such as humoral and cellular. This 
data will be used to inform future studies. Kaplan-Meier
30 survival curves will be used to 
estimate overall survival and progression-free survival.   We will also assess the rates of organ 
toxicity.  Cox proportional hazards regression analysis will be used to model the association 
between overall survival and progression-free survival and disease and demographic 
covariates of interest, including data from the correlative cytokine, immune, and Mir studies. 
10.0  Adverse Event Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide.  
 
 


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10.1 
Definitions  
 
10.1.1 Adverse Events 
 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 
1995). 
 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an adverse event term.  As an 
example, "worsening of underlying disease" or the clinical diagnosis that is associated with 
disease progression should be reported. 
Adverse events may include, but are not limited to: 
 
Subjective or objective symptoms provided by the patient and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
 
Any AEs experienced by the patient through the completion of final study procedures. 
 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period  
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
 
The following are NOT considered AEs: 
 
 
Pre-existing condition:  A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
 
Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after enrollment 
in the study for a condition that has not changed from its baseline level.  Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due to 
long travel distances are also not SAEs. 
 
Diagnostic Testing and Procedures:  Testing and procedures should not to be reported 
as AEs or SAEs, but rather the cause for the test or procedure should be reported. 
 
Asymptomatic Treatment Related Lymphocytosis: This event should also not be 
considered an AE.  Patients with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures. 


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10.1.2 Severity Criteria (Grade 1-5) 
 
Definitions found in the Common Terminology Criteria for Adverse Events (CTCAE v4.0) will be 
used for grading the severity (intensity) of nonhematologic AEs.  The CTCAE v4.0 displays 
Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE.  
Should a patient experience any AE not listed in the CTCAE v4.0, the following grading system 
should be used to assess severity: 
 
 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the patient’s daily activities 
 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the patient’s usual daily activity, and require systemic drug therapy or other 
treatment 
 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death 
 
Grade 5 (Death related to AE) – experiences which result in patient death 
10.1.3 Causality (Attribution)  
 
The Investigator is to assess the causal relation (i.e., whether there is a reasonable possibility 
that the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures.  Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes. 
Related: 
The AE is clearly related to use of the investigational product. 
 
10.2 
Unexpected Adverse Events 
 
An “unexpected” AE is an AE that is not listed in the package insert (Appendix C.) or is not 
listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the package insert referred only to 
elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 


2014-0096 
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vasculitis would be “unexpected” (by virtue of greater specificity) if the package insert listed 
only cerebral vascular accidents.  "Unexpected" also refers to AEs that are mentioned in the 
package insert as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the study drug under 
investigation. 
10.3 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
10.3.1 Assessment of Adverse Events 
Investigators will assess the occurrence of adverse events and serious adverse events at all 
subject evaluation time points during the study. All adverse events and serious adverse events 
whether volunteered by the subject, discovered by study personnel during questioning, 
detected through physical examination, clinically significant laboratory test, or other means, will 
be recorded. Each recorded adverse event or serious adverse event will be described by its 
duration (i.e., start and end dates), severity, regulatory seriousness criteria (if applicable), 
suspected relationship to the investigational product, and any actions taken. 
 
Adverse events will be documented and entered into the electronic case report form in MD 
Anderson’s PDMS/CORe systems and in the medical record. All protocol specific data will be 
entered into PDMS/CORe. 
10.3.2 Adverse Event Reporting Period 
 
All AEs whether serious or non-serious, will be captured from the first dose of study drug until 
30 days following the last dose of study drug and will be collected in MD Anderson’s Clinical 
Oncology Research (CORe) system.  We will record the AEs’ start date, resolution date, and 
maximum grade. 
 
Serious adverse events reported after 30 days following the last dose of study drug should also 
be reported if considered related to study drug. Resolution information after 30 days should be 
provided.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. (See Section 10.1.1) 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document. All records will need to 
capture the details of the duration and the severity of each episode, the action taken with 
respect to the study drug, investigator’s evaluation of its relationship to the study drug, and the 
event outcome. Whenever possible, diagnoses should be given when signs and symptoms are 
due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as "upper respiratory infection").  
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  


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If a death occurs within 30 days after the last dose of study drug, the death must be reported 
as a serious adverse event.  
10.3.3 Pregnancy 
 
Before study enrollment, subjects must agree to take appropriate measures to avoid 
pregnancy. However, should a pregnancy occur in a female study subject, consent to provide 
follow-up information regarding the outcome of the pregnancy and the health of the infant until 
30 days old will be requested. 
 
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 months 
after the last dose of study drug. Any female subjects receiving study drug(s) who become 
pregnant must immediately discontinue study drug. The Investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.   
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of 
consent to 30 days after the last dose of study drug must be reported. Any occurrence of 
pregnancy must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting 
timelines. All pregnancies will be followed for outcome, which is defined as elective termination 
of the pregnancy, miscarriage, or delivery of the fetus. Pregnancies with an outcome of live 
birth, the newborn infant will be followed until 30 days old by completing will need to be 
reported to Pharmacyclics per SAE reporting timelines. Any congenital anomaly/birth defect 
noted in the infant must be reported as a serious adverse event. 
10.3.4 Other Malignancies 
 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for overall survival. If observed, 
enter data in the corresponding eCRF. 
 
10.3.5 Adverse Events of Special Interest (AESI) 
 
Specific adverse events, or groups of adverse events, will be followed as part of standard 
safety monitoring activities. These 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 


2014-0096 
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*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 
or higher AE per CTCAE v4. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest as defined above. 
10.3.6 Serious Adverse Events (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
Death 
 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if 
deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of knowledge 
of the event). 
  
 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office.  
 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 


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 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
 
 
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
10.3.7   Investigator Communications with Pharmacyclics, Inc. 
 
All serious adverse events will be reported on the MD Anderson SAE Form and will be sent via 
email (AEintakePM@pcyc.com) or fax ((408) 215-3500) to Pharmacyclics Drug Safety, or 
designee within 15 days of the event.  Pharmacyclics may request follow-up and other 
additional information from the 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) 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
11.0 Study Administration and Principal Investigator Obligations 
 
Per the IST Agreement, 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.  Written 
verification of IRB approval will be obtained before any amendment is implemented. 
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