Clinical trial NCT02744612
Conditions: Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma
Sponsor: City of Hope Medical Center
Start date: 2016-06-20; Completion date: 2024-07-30
Enrollment: 39 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase II trial studies how well ibrutinib and brentuximab vedotin work in treating patients with Hodgkin lymphoma that has returned (relapsed) or does not respond to treatment (refractory). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as brentuximab vedotin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib together with brentuximab vedotin may be a better treatment for Hodgkin lymphoma.

Detailed description:
PRIMARY OBJECTIVE:

I. Evaluate the anti-tumor activity of the two agent combination ibrutinib and brentuximab vedotin, as assessed by complete response (CR) rate.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of the two agent combination through evaluation of toxicities, including type, frequency, severity, attribution, time course and duration.

II. Obtain estimates of overall response rate (ORR), response duration and survival (overall and progression-free).

III. Describe outcomes of patients who ultimately undergo autologous or allogeneic hematopoietic cell transplantation following treatment with ibrutinib/brentuximab vedotin.

EXPLORATORY OBJECTIVE:

I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and serial plasma samples for future biomarker evaluation.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21 and brentuximab vedotin intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Arms: arm 1: Patients receive ibrutinib 420 mg PO QD on days 1-21 and brentuximab vedotin 1.8 mg/kg IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ibrutinib 560 mg PO QD on days 1-21 and brentuximab vedotin 1.8 mg/kg IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Brentuximab Vedotin intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB 15334 
 
02-14-2020 
Version: 16 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HCT  
 
 
TITLE: A MULTI-CENTER PHASE II TRIAL OF IBRUTINIB PLUS BRENTUXIMAB VEDOTIN IN 
RELAPSED/REFRACTORY HODGKIN LYMPHOMA 
 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 15334  
 
 
 
VERSION: 16 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
COH Initial Approval 
Protocol Dated 02/15/2016 
Version: 00 
COH Amendment 01  
 
Protocol Dated 05/31/2016 
 
 
 
 
     Version: 01 
COH Amendment 02  
 
Title Page Dated 06/06/2016  
 
 
 
     Version: 02 
COH Amendment 03  
 
Title Page Dated 08/19/2016  
 
      
 
     Version: 03 
COH Amendment 04  
 
Protocol Dated 11/18/16 
 
 
 
 
     Version: 04 
COH Amendment 05  
 
Protocol Dated 04/10/2017 
 
 
 
 
     Version: 05 
COH Amendment 06                          Title Page Dated 07/25/2017 
           Version: 06 
COH Amendment 07                          Protocol Dated 12/26/2017              
 
 
     Version: 07 
COH Amendment 08                          Title Page Dated 01/04/2018 
           Version: 08 
COH Amendment 09                          Protocol Dated 03/06/2018              
 
 
     Version: 09 
COH Amendment 10                          Protocol Dated 05/16/2018              
 
 
     Version: 10 
COH Amendment 11  
 
Protocol Dated 11/26/2018 
 
 
 
 
     Version: 11 
COH Amendment 12  
 
Protocol Dated 12/13/2018 
 
 
 
 
     Version: 12 
COH Amendment 13                          Title Page Dated 05/21/2019 
           Version: 13 
COH Amendment 14                          Protocol Dated 10/29/2019 
           Version: 14 
COH Amendment 15                          Protocol Dated 11/07/2019 
           Version: 15 
COH Amendment 16 
Protocol Dated 02/14/2020 
Version: 16 
 
 
SITE:  
 
 
 
 
 
Hodgkin Lymphoma  
 
 
 
STAGE (If applicable): 
 
 
 
All 
 
 
 
MODALITY:  
 
 
 
 
Intravenous and Oral  
 
 
 
TYPE:  
 
 
 
 
 
Phase II Multi-center  
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Alex Herrera, M.D. 
 
 
 
COLLABORATING INVESTIGATOR(S): 
 
 
 
PARTICIPATING CLINICIANS: 
Leslie Popplewell, M.D., Tanya Siddiqi, M.D., Jasmine 
Zain, M.D., Elizabeth Budde, M.D., Matthew Mei, M.D., 
Eileen Smith, M.D., Stephen Forman, M.D., Steven Rosen, 
M.D., Larry Kwak, M.D., Saro Armenian, D.O., M.P.H., 
Liana Nikolaenko, M.D. , Geoffrey Shouse, D.O. 
 
COH BIOSTATISTICIAN(S):  
 
 
Joycelynne M. Palmer, PhD 
 


Page 1 of 67 
IRB Protocol No. 15334 
 
Version Date: 02/14/20 
Version: 16 
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
Department of Hematology/HCT 
 
TITLE:  
A MULTI-CENTER PHASE II TRIAL OF IBRUTINIB PLUS BRENTUXIMAB VEDOTIN 
IN RELAPSED/REFRACTORY HODGKIN LYMPHOMA  
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 15334  
 
VERSION: 16  
 
 
SPONSOR/IND NUMBER:   
N/A 
DISEASE SITE: 
Hodgkin Lymphoma  
DISEAS STAGE: 
All 
MODALITY: 
Intravenous and Oral 
PHASE/TYPE: 
Phase II/Multi-center 
PARTICIPATING SITES: 
City of Hope 
Cornell Medical College 
University of California, San Diego 
Ohio State University 
STUDY SPONSOR AND MONITOR: 
City of Hope 
Investigators 
Principal Investigator: 
Alex Herrera, MD 
 
City of Hope National Medical Center 
Hematologic 
Malignancies 
and 
Stem 
Cell 
Transplantation Institute 
1500 E. Duarte Road 
Duarte, CA 91010 
T: 626-256-4673 ext 82405 
F: 626-301-8116 
email: aherrera@coh.org 
 
 
Collaborating Biostatistician: 
Joycelynne M. Palmer, PhD 
City of Hope National Medical Center 
Hematologic Malignancies and Stem Cell 
Transplantation Institute 
1500 E. Duarte Road 
Duarte, CA 91010 
T: 626-256-4673 ext 84133 
F: 626-471-7106 
email: jmpalmer@coh.org  
 


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IRB Protocol No. 15334 
 
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Version: 16 
Collaborating Investigators: 
 
Peter Martin, MD 
Cornell Medical College 
Department of Medical Oncology 
525 East 68th Street 
Payson Pavilion, 3 
New York, NY 10065 
Phone: (646) 962-2064 
Fax: (646) 962-1605 
e-mail: pem9019Emed.cornell.edu   
Carolyn Mulroney, MD 
University of California San Diego 
Department of Medicine 
9500 Gilman Dr. #0960 
La Jolla, CA 92093 
T: 8588226600 
e-mail: camulroney@ucsd.edu 
 
Kami Maddocks, MD 
Division of Hematology 
Ohio State University Comprehensive Cancer 
Center  
Arthur G. James Cancer Hospital and Richard J. 
Solove Research Institute  
A457 Starling-Loving Hall 
320 W. 10th Avenue 
Columbus, Ohio 43210 
T: (614) 688-7942 
e-mail: kami.maddocks@osumc.edu  
 
 
AGENT NSC# / IND#: 
IND# 129787 
 
 
COORDINATING CENTER: 
 
Data Coordinating Center 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 
Phone: 626-218-7904 
E-mail: DCC@coh.org 


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IRB Protocol No. 15334 
 
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Experimental Design Schema 
 
Note: There is a lead in portion using only 420 mg oral daily and 560 mg daily.  


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IRB Protocol No. 15334 
 
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Protocol Synopsis 
Protocol Title: 
A multi-center phase II study of ibrutinib plus brentuximab vedotin in relapsed/refractory Hodgkin 
Lymphoma. 
Brief Protocol Title (Lay Public): 
A phase II study of ibrutinib plus brentuximab vedotin in high-risk Hodgkin Lymphoma  
Study Phase: 
Phase II with safety lead-in 
Participating Sites: 
 City of Hope  
 Cornell  
 UCSD 
 OSU 
Study Rationale: 
Brentuximab vedotin (BV) is an antibody drug conjugate (ADC) consisting of the chimeric 
antibody SGN-30 (cAC10) chemically conjugated to the anti-tubulin agent monomethyl auristatin 
E (MMAE). BV binds to CD30 on the cell surface of Hodgkin-Reed-Sternberg cells and is 
internalized. Upon trafficking to lysosomes, MMAE is released from the conjugate and disrupts 
the microtubule network.1 We previously participated in the multi-center phase II pivotal study 
investigating the use of single agent brentuximab vedotin (BV) in patients with relapsed/refractory 
Hodgkin lymphoma (HL) post autologous hematopoietic stem cell transplantation (AHCT). This 
trial showed that BV has an overall response rate of 75%, with a 34% complete response rate and 
tolerable toxicity.2 Because of the high response rate, BV was granted accelerated FDA approval 
for the treatment of relapsed/refractory HL following failed AHCT. Although this drug has high 
response rates in HL, the complete response rate and the duration of response can be improved. 
Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which inhibits activation of the B cell 
receptor signaling cascade. It has demonstrated activity in patients with relapsed/refractory B cell 
lymphomas3 and has already received FDA approval for the treatment of CLL and MCL.4,5 Ibrutinib 
is also an ITK inhibitor, which can be active against activated T cells. It is possible that ibrutinib 
can inhibit B cells and T cells in the microenvironment of HL. We performed a synergy assay 
testing the combination of ibrutinib and brentuximab vedotin (the latter previously known as SGN-
35) in L428 (HL cell line) and found a synergistic effect. Since there is evidence of synergy in 
preclinical studies and the toxicity profiles do not appear to be the similar, it is reasonable to 
combine the two agents in relapsed/refractory Hodgkin lymphoma.  
Objectives: 
In patients with relapsed/refractory Hodgkin Lymphoma: 
Primary: 
 
Evaluate the anti-tumor activity of the two agent combination ibrutinib and brentuximab 
vedotin, as assessed by complete response (CR) rate. 
Secondary: 
 
Assess the safety and tolerability of the two agent combination through evaluation of toxicities, 
including type, frequency, severity, attribution, time course and duration. 


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IRB Protocol No. 15334 
 
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 
Obtain estimates of overall response rate (ORR), response duration and survival (overall and 
progression-free). 
 
Describe outcomes of patients who ultimately undergo autologous or allogeneic hematopoietic 
cell transplantation following treatment with ibrutinib/brentuximab vedotin. 
Exploratory: 
 
Collect DNA/RNA from lymphoma specimens and serial plasma samples for future biomarker 
evaluation. 
 
Study Design: 
This study will be conducted as a multi-center phase II trial; a Simon Two-Stage (Minimax) Design 
will be employed. Prior to formally initiating the phase II trial, a patient safety lead-in segment will 
be conducted to ensure there are no unexpected toxicities during cycle 1. Ultimately a total of 39 
patients will be treated and evaluated for response at the ibrutinib/brentuximab vedotin doses 
considered safe -as determined during the safety lead-in segment of this study. 
 
The first nine to twelve patients enrolled will be part of the patient safety lead-in. Initially, a group 
of up to 3 patients can be enrolled. Because both brentuximab vedotin and ibrutinib have been 
extensively studied as single agents with tolerable toxicity profiles, it is assumed that the standard 
FDA-approved dosing would be tolerable (dose level 2: Ibrutinib 560mg/brentuximab vedotin 
1.8mg/kg). However, during the safety lead in patients will initially be treated with 420 mg of 
Ibrutinib (dose level 1).   
  
Following the safety lead-in, the phase II trial will formally be initiated. In the first stage, 19 patients 
will be entered on the study. If ≤ 6 complete responses are seen, the study will be terminated. If at 
least 7 patients achieve a complete response, the trial will continue to the second stage. At stage 2, 
20 additional patients will be entered. At the end of stage 2, if 17 or more patients experience a 
complete response, the combination will be considered worthy of further study.  If ≤ 16 patients 
experience a complete response then no further investigation of the combination is warranted. 
 
In addition to response assessment, using the Cheson Criteria (Cheson et al. 2014)24, survival, 
toxicity information, and lymphoma specimens/plasma samples will be collected for exploratory 
biomarker evaluation. 
Endpoints: 
The primary study endpoint is complete response (CR) rate and is based on the Cheson Criteria 
(Cheson et al. 2014)24. 
The primary endpoint for the patient saftey lead-in segment of the study is toxicity. Toxicity will 
be scored using the NCI CTCAE v4.0 Scale. Unacceptable toxicity in a given patient is defined as 
any non-hematologic grade 3|4 toxicity or, for hematologic toxicities, any grade 3|4 that does not 
resolve to a grade 1|2 within 7 days per NCI CTCAE v4.03 toxicity criteria and is considered at 
least possibly related to ibrutinib and/or brentuximab vedotin, or any other regimen-related cause 
of death. 
Sample Size: 
Assuming 1) the ibrutinib 560mg and brentuximab vedotin 1.8mg/kg doses are well tolerated and 
2) the study does not close for futility, 39 evaluable (received at least one cycle of treatment) 
patients will be enrolled on the phase II portion of the study. Note: Expected accrual for safety lead-
in segment: n=9.  


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Estimated Duration of the Study 
In the event that the study does not close for futility, accrual is expected to be completed in 45 
months; with approximately 1-2 patients enrolled each month. Patients will be treated in 21-day 
treatment cycles until disease relapse, progression, unacceptable toxicity, or withdrawal of consent. 
Patients who discontinue study treatment for reasons other than disease relapse/progression will 
continue to have disease assessments per Cheson criteria24 until relapse or progression, initiation 
of new anticancer treatment, or death whichever occurs first. Patients will be followed to collect 
further anticancer treatment (including HCT) and survival information until death, loss to follow-
up, withdrawal of consent, study termination or up to 24 months post completion/ discontinuation 
of treatment. 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
1) Relapsed/refractory biopsy-proven CD30+ Hodgkin Lymphoma 
2) Age > 15 years old and > 40kg 
3) ECOG Performance status 0-2 
4) Prior exposure to brentuximab vedotin (relapsed disease after 3 month, not refractory 
disease) is allowed 
5) Prior autologous hematopoietic cell transplant is allowed 
6) Prior allogeneic hematopoietic cell transplant (allo-HCT) is allowed, provided there is no 
active GVHD and the patient is not taking immunosuppressive agents. Patient has to be at 
least 3 months out of allo-HCT.    
7) Prior radiation therapy is allowed. 
8) Patients may be on steroids before initiation of treatment, provided that use was tapered 
down to ≤20 mg prednisone or equivalent by cycle 1 day 1. 
Exclusion Criteria: 
1) Patients may not have developed progressive disease with prior treatment with 
brentuximab vedotin and may not have hypersensitivity to the drug. Prior ibrutinib for HL 
is not allowed. 
2) Age < 15 years old or <40kg 
3) Patients may not be taking other investigational products or concurrent biological therapy, 
chemotherapy, or radiation therapy. 
4) Platelet count < 50,000, ANC <  1,000, hemoglobin <  8.5. (Growth factor support or 
transfusions to achieve targets are allowed provided that they have not received growth 
factor support for at least 14 days prior to entering trial) 
5) Patients should not have any uncontrolled illness or active infection, including detectable 
HIV, HCV, and HBV. Patients with recent infection requiring systemic treatment that was 
completed ≤ 14 days before the first dose of study drugs are ineligible. 
6) Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03) grade 0 or 1, or 
to the levels dictated in the inclusion/exclusion criteria with the exception of stable 
neuropathy, vitiligo, alopecia, or other irreversible toxicity not reasonably expected to be 
exacerbated by study treatment (e.g., hearing loss)  
7) Patients must not be vaccinated with live, attenuated vaccines with 4 weeks of the first dose 
of the study drugs. 
8) Patients with active CNS disease or history of brain metastases are ineligible. 


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IRB Protocol No. 15334 
 
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9) Patients must not have another malignancy within 3 years of enrollment. Exceptions: 
complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in 
situ malignancy, or low-risk prostate cancer after curative therapy. 
10) Pregnant women are excluded from the study. 
11) Patients with a myocardial infarction within 6 months, or those with severe or poorly 
controlled cardiovascular illness are ineligible. 
12) Patients must not have baseline grade II peripheral neuropathy. 
13) Patients must not have known bleeding disorders, or history of stroke or intracranial 
hemorrhage within 6 months before enrollment. 
14) Concomitant use of warfarin or other vitamin K antagonists is not allowed. Patients 
requiring treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor are ineligible. (see 
Appendix 1) 
15) Unable to swallow capsules or malabsorption syndrome, disease or condition significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, or partial or 
complete bowel obstruction 
16) Currently active, clinically significant hepatic impairment Child-Pugh class B or C 
according to the Child Pugh classification 
 
Investigational Product Dosage and Administration: 
 
Ibrutinib 560mg orally daily (expected dose, phase II) 
 
Ibrutinib  420mg and 560mg orally daily (planned doses, safety lead-in)   
 
Brentuximab vedotin (commercial supply) 1.8mg/kg intravenously every 3 weeks   
 
1 cycle = 21 days 
Clinical Observations and Tests to be Performed: 
Physical exams, tumor measurements by radiographic imaging, blood tests to examine toxicities, 
and analysis on lymphoma specimens.  See section 9.0 for details.  
Statistical Considerations: 
The primary hypothesis is that, in patients with relapsed/refractory Hodgkin Lymphoma (HL), the 
two agent combination ibrutinib and brentuximab vedotin (BV) can increase the complete response 
(CR) rate. 
In a multi-center phase II trial investigating the use of single agent BV in relapsed/refractory HL 
patients post-AHCT, the overall response rate was 75%, the CR rate was 34%.2 Although single 
agent BV therapy is associated with a high overall response rate and tolerable toxicity, the CR rate 
and the duration of response can be improved. 
The primary objective is to evaluate the antitumor activity of the two agent combination ibrutinib 
and brentuximab vedotin, as assessed by complete response (CR) rate, in patients with 
relapsed/refractory HL. The primary endpoint is a confirmed tumor response of CR and is based 
on the Cheson Criteria24. A single cycle of treatment will be given in a 21 day cycle. Each patient’s 
disease status will be evaluated at baseline; response will be assessed as outlined in the study 
schema. 
Statistics/Sample Size and Accrual: This study will implement a Simon Two-Stage (Minimax) 
Design30,31 to evaluate the activity of the two agent combination ibrutinib and brentuximab vedotin. 
The null hypothesis that the true CR rate is 30% will be tested against a one-sided alternative. The 
phase II portion of the study is expected to enroll a minimum of 19 and a maximum of 39 patients. 


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The sample size is based on the desire to discriminate a promising CR rate of 50% from a 
disappointing response rate of 30% using a type I error rate of 0.05 and power of 80%.  
During the first stage, 19 patients will be entered on the study. If ≤ 6 complete responses are seen, 
the study will be terminated. If at least 7 patients achieve a complete response, the trial will continue 
to the second stage.  
At the second stage, 20 additional patients will be entered. At the end of stage 2, if 17 or more 
patients experience a complete response, the combination will be considered worthy of further 
study.  If ≤16 patients experience a complete response then no further investigation of the 
combination is warranted.  A total of 39 patients will be included in the phase II portion of trial.  
The study will also have a lead in phase where a minimum of three patients will be enrolled with 
420 mg oral daily dosing of ibrutinib.  
Analysis: All patients who met the eligibility criteria (with the exception of those who received no 
study medication) will be included in the main analysis of response and survival endpoints and all 
of the secondary or correlative analysis described below.   
Sponsor/Licensee: 
This is a COH investigator initiated trial with COH holding the IND and Pharmacyclics providing 
funding support and drug supply. 
Case Report Forms 
Medidata Rave EDC® 


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IRB Protocol No. 15334 
 
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Table of Contents 
 
SECTION ................................................................................................................................. PAGE 
1.0 
Goals and Objectives ........................................................................................................ 14 
2.0 
Background ....................................................................................................................... 14 
2.1 
Introduction/Rationale for Development ............................................................. 14 
2.2 
Overview of Proposed Study ............................................................................... 16 
2.3 
Preclinical Studies ................................................................................................ 16 
2.3.1 .... Brentuximab vedotin............................................................................... 16 
2.3.2 .... Ibrutinib .................................................................................................. 17 
2.4 
Human Studies ..................................................................................................... 18 
2.4.1 .... Brentuximab vedotin............................................................................... 18 
2.4.2 .... Ibrutinib .................................................................................................. 19 
3.0 
Patient Eligibility .............................................................................................................. 22 
3.1 
Inclusion Criteria ................................................................................................. 22 
3.1.1 .... Child Bearing Potential ........................................................................... 23 
3.1.2 .... Informed Consent/Assent ....................................................................... 23 
3.1.3 .... Prior Therapy .......................................................................................... 23 
3.2 
Exclusion Criteria ................................................................................................ 23 
3.2.1 .... Study-Specific Exclusions ...................................................................... 24 
3.2.2 .... Non-Compliance ..................................................................................... 25 
3.3 
Inclusion of Women and Minorities .................................................................... 25 
4.0 
Participant Enrollment ...................................................................................................... 25 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ............................ 25 
4.2 
Participant registration ......................................... Error! Bookmark not defined. 
4.2.1 .... COH DCC Availability and Contact InformationError! Bookmark not defined. 
4.2.2 .... Slot verification and reservation ............................................................. 25 
4.2.3 .... Registration procedure ............................................................................ 25 
4.3 
Dose Level Assignment ....................................................................................... 26 
5.0 
Treatment Program ........................................................................................................... 26 
5.1 
Treatment Overview ............................................................................................ 26 
5.1.1 .... Brentuximab vedotin Dose and Administration ..................................... 26 
5.1.2 .... BV Required Premedication and Postmedication ................................... 27 


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5.1.3 .... BV Management of Infusion Reactions .................................................. 27 
5.1.4 .... Ibrutinib (to be given prior to infusion with BV) ................................... 27 
5.1.5 .... Dose and Administration ........................................................................ 27 
5.1.6 .... Overdose ................................................................................................. 28 
5.1.7 .... Schedule .................................................................................................. 28 
5.2 
Planned Duration of Therapy ............................................................................... 29 
5.3 
Criteria for Removal from Treatment .................................................................. 29 
5.4 
Subject Follow-Up ............................................................................................... 29 
5.5 
Supportive Care, Other Concomitant Therapy, Prohibited Medications ............. 29 
6.0 
Dose Modification for Adverse Events ............................................................................. 31 
6.1 
Anticipated Toxicities .......................................................................................... 31 
6.1.1 .... Ibrutininb ................................................................................................ 31 
6.1.2 .... Brentuximab Vedotin .............................................................................. 32 
7.0 
Agent Information and Risks ............................................................................................ 35 
7.1 Brentuximab vedotin ................................................................................................... 35 
7.1.1 .... Description .............................................................................................. 35 
7.1.2 .... Toxicology .............................................................................................. 35 
7.1.3 .... Pharmacology – Handling, Storage, Dispensing and Disposal ............... 35 
7.2 
Ibrutinib ............................................................................................................... 35 
7.2.1 .... Description .............................................................................................. 35 
7.2.2 .... Toxicology .............................................................................................. 36 
7.2.3 .... Pharmacology-Handling, Storage, Dispensing, and Disposal: ............... 36 
8.0 
Correlative/Special Studies ............................................................................................... 36 
9.0 
Study Calendar .................................................................................................................. 38 
10.0 
Endpoint Evaluation Criteria/Measurement of Effect....................................................... 39 
10.1 
Definitions ........................................................................................................... 39 
10.2 
Transplant Endpoint Definitions .......................................................................... 39 
10.3 
Response Criteria and Methods for Evaluation of Measurable Disease .............. 40 
11.0 
Statistical Considerations .................................................................................................. 40 
11.1 
Study Design ........................................................................................................ 40 
11.1.1  Phase II .................................................................................................... 40 
11.1.2  Safety Lead-In .......................................................................................... 41 
11.2 
Sample Size Accrual Rate .................................................................................... 41 
11.3 
Safety Analysis and Stopping Rules for Excessive Toxicity ............................... 42 


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11.4 
Statistical Analysis Plan ....................................................................................... 42 
11.5 
Analysis of Correlative Endpoints: ...................................................................... 42 
12.0 
Data Handling, Data Management, Record Keeping ........................................................ 42 
12.1 Source Documents .................................................................................................... 42 
12.2 Data Capture Methods and Management .................................................................. 42 
12.3 Case Report Forms/Data Submission Schedule ........................................................ 43 
12.4 Regulatory Records ................................................................................................... 44 
13.0 
Unanticipated Problems and Adverse Event Reporting .................................................... 44 
13.1 
Definitions ........................................................................................................... 44 
13.1.1 .. Adverse Event (AE) ................................................................................ 44 
13.1.5.1 Major Hemorrhage ................................. Error! Bookmark not defined. 
13.2 
Reporting of Non-Serious Adverse Events .......................................................... 46 
13.3 
Reporting of Serious Adverse Events and Unanticipated Problems by Site Principal 
Investigators ......................................................................................................... 47 
13.4 
Reporting of Serious Adverse Events and Unanticipated Problems by Overall Study 
Principal Investigator: .......................................... Error! Bookmark not defined. 
12.1.1 .. Reporting to COH IRB ........................................................................... 48 
12.1.2 .. Reporting to COH DSMC ....................... Error! Bookmark not defined. 
12.1.3 .. Reporting to the FDA ............................................................................. 48 
12.1.4 .. Reporting to Participating Investigators ................................................. 48 
12.1.5 .. Reporting to Pharmacyclics .................................................................... 49 
14.0 
Protocol Deviations and Single Subject Exceptions ......................................................... 49 
14.1 
Definitions ........................................................................................................... 49 
14.1.1 .. Deviation ................................................................................................. 49 
14.2 
Reporting Deviations ........................................................................................... 49 
14.3 
Reporting Single Subject Exceptions (SSEs) ...................................................... 50 
14.4 
Resolving Discrepancies ...................................... Error! Bookmark not defined. 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring .............................. 50 
15.1 
Site Principal Investigator .................................................................................... 50 
15.2 
Study Principal Investigator ................................................................................. 51 
15.3 
Protocol Management Team (PMT) .................................................................... 51 
15.4 
Monitoring ........................................................................................................... 51 
15.5 
Quality Assurance ................................................................................................ 51 
15.6 
City of Hope Data and Safety Monitoring Committee ........................................ 51 


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16.0 
Ethical and Regulatory Considerations ............................................................................. 52 
16.1 
Ethical Standard ................................................................................................... 52 
16.2 
Regulatory Compliance ....................................................................................... 52 
16.3 
Institutional Review Board .................................................................................. 53 
16.4 
Informed Consent ................................................................................................ 53 
16.5 
Recruitment of Subjects ....................................................................................... 53 
16.6 
Advertisements .................................................................................................... 54 
16.7 
 Study Location and Performance Sites ............................................................... 54 
16.8 
Participant Confidentiality ................................................................................... 54 
16.9 
Financial Obligations and Compensation ............................................................ 54 
17.0 
References ......................................................................................................................... 56 
  
Appendix 1: Inhibitors and Inducers of CYP3A ………………………………………………….57 
Appendix 2:  PD Sample Collection Procedures………………………………………………….59 
Appendix 3: Tissue Shipping Guidelines to City of Hope Pathology Core …….………………61 
Appendix 4: Blood Shipping Guidelines to City of Hope APCF ….…………….………………62 
Appendix 5:  SAE/UP Reporting Coversheet…………………………………….……………….63 
Appendix 6:  Registration Coversheet……………………….………………………..……….….64 
Appendix 7:  Supplemental Materials…………………….…………………….…………………65 


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Abbreviations 
Abbreviation 
Meaning 
AE 
BV 
Adverse Event 
Brentuximab Vedotin 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
 


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1.0 
Goals and Objectives 
In relapsed/refractory Hodgkin Lymphoma patients: 
Primary Objective: 
 
Evaluate the anti-tumor activity of the two agent combination ibrutinib and brentuximab vedotin, as 
assessed by complete response (CR) rate. 
Secondary Objectives: 
 
Assess the safety and tolerability of the two agent combination through evaluation of toxicities, 
including type, frequency, severity, attribution, time course and duration. 
 
Obtain estimates of overall response rate (ORR), response duration and survival (overall and 
progression-free). 
 
Describe outcomes of patients who ultimately undergo autologous or allogeneic hematopoietic cell 
transplantation following treatment with ibrutinib/brentuximab vedotin. 
Exploratory Objective: 
 
Collect DNA/RNA from lymphoma specimens and serial plasma samples for future biomarker 
evaluation. 
2.0 
Background 
2.1 Introduction/Rationale for Development 
Hodgkin Lymphoma: 
Hodgkin lymphoma (HL) is a neoplasm of lymphoid tissue that is histopathologically defined by the 
presence of malignant Hodgkin-Reed-Sternberg (HRS) cells in a background of inflammatory cells.6 The 
characteristic surface antigen expressed on HRS cells is CD30. In 2008, it was estimated that approximately 
8,220 new cases of HL would be diagnosed in the United States and 1,350 patients would die of their 
disease.7 It was also estimated that approximately 7,882 new cases of HL would be diagnosed in 2008 in 5 
major EU countries (UK, France, Germany, Italy, and Spain; Mattson Jack’s Cancer Impact Epidemiology 
Database).8 Similarly, it was estimated that approximately 890 new cases of HL would be diagnosed in 
2008 in Canada and 110 would die of their disease.9  
Advances in the use of combined chemotherapy and radiotherapy in HL over the past half-century have 
resulted in a durable remission rate of approximately 70%.6 However, these multi-agent regimens are 
associated with significant morbidity, including secondary malignancies, cardiac disease, pulmonary 
disease, and infertility.10-12 Furthermore, approximately 30-40% of patients presenting with HL will become 
refractory to initial therapy or will relapse. The therapeutic options for patients with refractory or relapsed 
disease are very limited and carry a high morbidity rate.13,14 
Brentuximab vedotin: 
Brentuximab vedotin (BV), previously known as SGN-35, is an antibody-drug conjugate (ADC) consisting 
of the chimeric antibody SGN-30 (cAC10) chemically conjugated to a synthetic analog (monomethyl 
auristatin E [MMAE]) of the naturally occurring antitubulin agent, dolastatin 10.15 Brentuximab vedotin is 
proposed to have a multi-step mechanism of action that is initiated by binding to CD30 on the cell surface 
and internalization of the ADC. Upon trafficking to lysosomes, MMAE is released from the conjugate 
through proteolytic degradation of the drug linker.1 Binding of released MMAE to tubulin disrupts the 
microtubule network, leading to G2/M phase cell cycle arrest and apoptosis.15  
Preclinical studies of brentuximab vedotin demonstrated antitumor activity in both in vitro and in vivo 
models. In a Phase 1 dose-escalation study of brentuximab vedotin administered IV every 21 days (SGN35-
0001), 45 patients were treated. The dose-limiting toxicity (DLT) experienced in the first cycle of therapy 
was more common at the 2.7 mg/kg dose level than at the 1.8 mg/kg dose level. DLTs observed in 3 of 12 


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patients treated at the 2.7 mg/kg dose level included Grade 4 neutropenic fever, Grade 3 prostatitis, Grade 
3 hyperglycemia, and 1 case of unrelated acute renal failure. One occurrence of Grade 4 thrombocytopenia 
qualified as a DLT at the 1.8 mg/kg dose level. The maximum tolerated dose (MTD) was defined as 1.8 
mg/kg IV administered every 3 weeks.16 
Phase II experience: 102 patients were treated in a multicenter pivotal phase II study of brentuximab 
vedotin. The dosing level and schedule was brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks. 
The overall response rate was 75%, with a 34% complete response rate and tolerable toxicity.2 The toxicity 
profile is similar to the phase I experience published by Younes et al.16 Because of the high response rate 
and tolerability, BV was granted accelerated FDA approval for the treatment of relapsed/refractory HL 
following failed AHCT.   
Although this drug has high response rates in HL, the complete response rate and the duration of response 
can both be improved. Among patients who only achieve a best response of partial remission, almost all 
eventually develop progressive disease.2 We have performed tumor biopsies on patients with recurrent and 
progressive HL (status post-treatment) with brentuximab vedotin; interestingly, surface CD30 expression 
still exists.17 It appears that CD30 targeting can still be utilized in this group of patients, but we must add 
other agents to increase the activity of brentuximab vedotin in this setting. Thus, it is important that we find 
a logical combination treatment strategy. 
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.18 In vitro, ibrutinib inhibits purified BTK and selected members of the kinase 
family, with 10-fold specificity over non-BTK kinases. Ibrutinib (IMBRUVICA®) is approved by the 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), and 3) CLL in patients with 17p 
deletion and 4) Waldenström’s Macroglobulinemia. Ibrutinib is currently under investigation for 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 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.19 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. 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.20   
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 this study, 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. 


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For the most comprehensive nonclinical and clinical information regarding ibrutinib background, safety, 
efficacy, and in vitro and in vivo preclinical activity and toxicology, refer to the latest version of the 
ibrutinib Investigator's Brochure.21 
We performed a synergy assay testing the combination of ibrutinib and brentuximab vedotin (SGN-35) in 
L428 (HL cell line) and found a synergistic effect. The CI was 0.253 for brentuximab vedotin 1: ibrutinib 
1, which is highly synergistic. Ibrutinib is also an ITK inhibitor, which can be active against activated T 
cells.22,23 It is possible that ibrutinib can inhibit B cells and T cells in the microenvironment of HL. Because 
of our in vitro synergy data, and because the two agents have a tolerable toxicity profile with little overlap, 
we propose a phase II study of ibrutinib plus brentuximab vedotin in patients with relapsed/refractory HL.  
 
 
2.2 Overview of Proposed Study 
This is an open label, multi-center phase II study of ibrutinib and brentuximab vedotin in patients with 
relapsed/refractory Hodgkin lymphoma. Ibrutinib will be given 560mg orally daily; brentuximab vedotin 
will be administered intravenously at 1.8mg/kg once on the first day of each cycle. Each cycle is 21 days. 
The primary efficacy endpoint of this study is complete response rate. Response will be assessed according 
to modified criteria for malignant lymphoma, based on (Cheson et al. 2014) and (Cheson et al. 2007).24,25 
Response assessment will be performed after cycles 2, 4, 7, 10, 13, and 16. Patients who achieve complete 
response (CR) can stop treatment after they have received 2 cycles of therapy post CR and at least 4 cycles 
of treatment. For patients who develop progressive disease while off treatment, they can return to treatment 
again provided that they have not received other investigational agents during the period of the protocol. 
(Autologous stem cell transplantation or allogeneic stem cell transplantation are allowed).  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
2.3 Preclinical Studies 
2.3.1 
Brentuximab vedotin 
Preclinical studies of brentuximab vedotin demonstrated antitumor activity in both in vitro and in vivo 
models. The toxicity of multiple doses of brentuximab vedotin has been assessed in rats and monkeys. In 
both species, hypocellularity of the bone marrow and lymphoid depletion of the thymus were observed. 


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Histopathologic lesions were also observed in the spleen in monkeys and in the liver and testes in rats. In 
addition, decreases in peripheral blood counts were observed in both species, and elevations in liver 
enzymes were seen in rats only. The most significant clinical toxicity was neutropenia, observed in 
monkeys, which resulted in secondary bacterial infections leading to early deaths at the 6 mg/kg dose. 
Toxicity was dose-dependent, with a no-observable-adverse-effect level of 0.5 mg/kg in rats and 1 mg/kg 
in monkeys. See the brentuximab vedotin SGN-35 Investigator’s Brochure for details of the nonclinical 
data.26 
2.3.2 
Ibrutinib 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of BTK.27 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.28 
For more detailed and comprehensive information regarding nonclinical pharmacology, refer to the current 
Investigator’s Brochure. 
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.   
On the basis of data from rats and dogs, 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 
doses that result in approximately 6 times and 14 times the exposure (AUC) in patients administered the 
daily dose of 420 and 560 mg, respectively.     
2.3.2.1 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 
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2.4 Human Studies 
2.4.1 
Brentuximab vedotin 
In the Phase 1 dose-escalation study of brentuximab vedotin administered IV every 21 days (SGN35-0001), 
45 patients were treated. The dose-limiting toxicity (DLT) experienced in the first cycle of therapy was 
more common at the 2.7 mg/kg dose level than at the 1.8 mg/kg dose level. DLTs observed in 3 of 12 
patients treated at the 2.7 mg/kg dose level included Grade 4 neutropenic fever, Grade 3 prostatitis, Grade 
3 hyperglycemia, and 1 case of unrelated acute renal failure. One occurrence of Grade 4 thrombocytopenia 
qualified as a DLT at the 1.8 mg/kg dose level. The maximum tolerated dose (MTD) was defined as 1.8 
mg/kg IV administered every 3 weeks. 
Phase II experience: 102 patients were treated in a multicenter pivotal phase II study of brentuximab 
vedotin. The dosing level and schedule was 102 patients relapsed post ASCT, using brentuximab vedotin 
1.8 mg/kg intravenously every 3 weeks. The overall response rate was 75%, with 34% complete response 
rate and tolerable toxicity.2 The toxicity profile is similar to the phase I experience published by Younes et 
al. (2010).16 Treatment-emergent AEs (TEAEs) occurring in ≥20% of patients in the phase 2 studies were 
peripheral sensory neuropathy (44%), fatigue (42%), nausea (41%), diarrhea (34%), pyrexia (31%), upper 
respiratory tract infections (28%), neutropenia (21%), and vomiting (20%). These events were primarily 
mild to moderate and reversible. Approximately half of patients had treatment-emergent peripheral 
neuropathy, predominantly sensory neuropathy, with an onset and severity pattern consistent with a 
cumulative effect. Dose delay and subsequent reduction to 1.2 mg/kg was generally effective in managing 
peripheral neuropathy. Grade 3 and 4 neutropenia occurred in 13% and 7% of patients, respectively; these 
events were typically of short duration and well managed by brief dose delays with growth factor support 
in some cases. Infusion-related reactions occurred in approximately 10% of patients and were typically 
managed by dose interruption. Infusion-related reaction prophylaxis in subsequent treatment cycles was 
instituted at the discretion of the investigator. The clinical laboratory parameters for which the most patients 
had new or worsening shifts to ≥Grade 3 were low neutrophils (11%), lymphocytes (11%), platelets (6%), 
and leukocytes (5%); and high glucose levels (6%). Only 1 patient in the phase 2 studies had Grade 3 
alanine aminotransferase (ALT) and Grade 3 aspartate aminotransferase (AST) levels. In the phase 2 
studies, 31% of patients had an SAE, 28% had a Grade 3 or higher SAE, and 15% had an SAE that was 
determined by the investigator to be related to brentuximab vedotin. The most common SAE preferred 
terms (2%) were abdominal pain, disease progression (recurrent sALCL), pulmonary embolism, and septic 
shock. A higher proportion of patients with sALCL experienced SAEs, including deaths within 30 days of 
last dose, relative to patients with HL, likely due to the older age and the more aggressive nature of the 
malignancy in this patient population. Because of the high response rate and tolerability, BV was granted 
accelerated FDA approval for the treatment of relapsed/refractory HL following failed AHCT.   
Pediatric experience: Fanale et al (2011) conducted a retrospective analysis of two phase 1 and two phase 
2, multicenter brentuximab vedotin drug development studies which included the enrollment of pediatric 
patients age 12-17 years old.29 Nine patients (median age=16 years, male=5) were included in this analysis. 
Patients received brentuximab vedotin, as a 30 minute outpatient infusion, at a dose of either 0.8 mg/kg or 
1.2 mg/kg weekly for 3 out of 4 weeks or doses of 1.2 mg/kg or 1.8 mg/kg every 3 weeks (median of 15 
cycles). The majority (n=6) of patients received 1.8 mg/kg every 3 weeks. Complete response was observed 
in 6/9 pediatric patients who had treatment-refractory lymphoma. Grade >3 treatment-emergent adverse 
events included neutropenia (n=3), decreased white blood cell count (n=1), thrombocytopenia (n=1), 
catheter site infection (n=1), and hyperesthesia (n=1). No patient discontinued treatment because of an 
adverse event.   
Although this drug has high response rates in HL, the complete response rate and the duration of response 
can both be improved. Among patients who only achieve a best response of partial remission, almost all 
eventually develop progressive disease.2 We have performed tumor biopsies on patients with recurrent and 


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progressive HL (status post treatment) with brentuximab vedotin; interestingly, surface CD30 expression 
still exists.17 It appears that CD30 targeting can still be utilized in this group of patients, but we must add 
other agents to increase the activity of brentuximab vedotin in this setting. Thus, it is important that we find 
a logical combination treatment strategy.  
This study will include patients eligible for both autologous and allogeneic stem cell transplantation.  We 
have already shown that brentuximab vedotin as a single agent can successfully enables patients to undergo 
either allogeneic stem cell transplantation or autologous stem cell transplantation (32,33).  Brentuximab 
vedotin is already included in the NCCN guideline as second line therapy in 2015 based on two publications 
(33,34).  We also know that patients who have chemosensitive disease at the time of transplantation have 
improved outcomes post transplantation (32,34). We are allowing patients who achieved PR or CR to the 
combination of brentuximab vedotin and ibrutinib be able to go onto autologous or allogeneic stem cell 
transplantation.   
2.4.2 
Ibrutinib 
Ibrutinib is under late-stage development as a single orally administered anticancer agent with lead 
indications in the relapsed/refractory setting and for treatment-naïve patients with B cell malignancies. 
Combination studies with chemoimmunotherapy and immunotherapy have been initiated. There are 20 
ongoing and 4 company-sponsored trials as of the 6 April 2014 data cutoff date; 26 ongoing and 9 completed 
company-sponsored clinical trials have investigated the safety, efficacy, and pharmacokinetics (PK) of 
ibrutinib in humans as a single agent and in combination with chemotherapy and immunotherapy. Across 
all studies, malignancies under investigation include CLL, small lymphocytic lymphoma (SLL), MCL, 
diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), multiple myeloma (MM),. As of the 
data cut-off of 6 April 2013, safety data are available for 736 subjects administered ibrutinib: 506 subjects 
receiving ibrutinib monotherapy, 100 healthy subjects summarized in the PK/clinical pharmacology 
studies, and 130 subjects receiving ibrutinib in combination with 1 or more marketed 
chemo/immunotherapeutic agents. In addition, approximately 537 subjects have been treated with ibrutinib 
or placebo in 5 randomized, controlled trials. In Study PCYC-1103-CA, the current version of the rollover 
extension study, 196 subjects continue to be treated with ibrutinib. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, refer to the current version of the 
Investigator's Brochure.  
Pharmacokinetics and Product 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 a 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 


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than 30 mL/min creatinine clearance). There are no data in patients with severe renal impairment or patients 
on dialysis. The study of ibrutinib in hepatic impaired subjects is currently in progress. 
Summary of Clinical Safety  
Pooled safety data for a total of 423 subjects treated with various therapies in combination with ibrutinib 
from 4 studies, which included1 randomized-control study, are summarized below.  Therapies used in 
combination with ibrutinib in these studies, included BR, FCR, ofatumumab, and R-CHOP. The median 
duration of treatment for this pool was 14.0 months (range: 0.2 to 27.1 months).  Refer to the ibrutinib IB, 
edition 9.0, dated 30 June 2015 for additional details concerning these studies 
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving ibrutinib in 
combination therapy (N=423): 
Most frequently reported TEAEs 
> 10%   
Most frequently reported Grade 
3 or 4 TEAEs > 2%  
Most frequently reported 
Serious TEAEs > 1%  
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension  
 
For more detailed information refer to the current version of the Investigator’s Brochure. 
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. Subjects with congenital bleeding diathesis have 
not been studied.  
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. 
In particular, subjects with a history of cardiac arrhythmias should be monitored closely. For atrial 
fibrillation which persists, consider the risks and benefits of ibrutinib treatment and follow the protocol 
dose modification guidelines.  
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were reported 
in subjects treated with ibrutinib.  
Diarrhea 


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Diarrhea is the most frequently reported nonhematologic 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, ibrutinib treatment should follow the 
protocol dose modification guidelines. 
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 v4.03). 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. 
Liver Failure 
Rare cases of liver failure have been reported in patients treated with ibrutinib. 
Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients 
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.  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.  
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. 
Lymphocytosis and Leukostasis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from baseline 
and an absolute count >5000/mcL), often associated with reduction of lymphadenopathy, has been observed 
in most subjects with CLL/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, >400000/mcL) 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. 


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Interstitial lung disease 
 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with 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 (eg, dyspnea, cough or pyrexia) and treated symptomatically, including interruption of the 
suspected agent as appropriate. 
3.0 
Patient Eligibility 
The eligibility criteria listed below are interpreted literally and cannot be waived. An abnormal test (such 
as a WBC) may be repeated, or a low hemoglobin or platelet count may be corrected with transfusion to 
make the patient eligible for study. Tests should be performed within 10 days of study entry. (For patients 
who re-enter the study after receiving autologous or allogeneic transplantation, they will be re-screened for 
eligibility per the inclusion and exclusion criteria).   
3.1 Inclusion Criteria  
 
Patients must have histologically documented or cytologically confirmed Hodgkin lymphoma with 
CD30 expression.   
 
Patients must have ANC >1000/μL, Plt > 50,000/μL, and hemoglobin > 8.5 g/dl. Neupogen can be 
given before and during treatment to achieve target ANC > 1000/uL. Platelet transfusion and 
packed red blood cell transfusion can also be given prior to the start of treatment and during 
treatment to achieve a target plt > 50,000/uL and hemogloblin of > 8.5/ul provided that patients 
have not received growth factors for at least 14 days prior to entering trial.   
 
Patients must have measurable disease > 1.5 cm evidenced by CT scan of the neck/chest/abd/pelvis 
or CT/PET scans. 
 
Patients must be either refractory to or relapsed after 1 line of therapy.   
 
Prior radiation therapy is allowed.   
 
Voluntary written informed consent before performance of any study-related procedure not part of 
normal medical care, with the understanding that consent may be withdrawn by the subject at any 
time without prejudice to future medical care. 
 
Female subject is either post-menopausal, surgically sterilized, or willing to use an acceptable 
method of birth control (i.e. a hormonal contraceptive, intra-uterine device, diaphragm with 
spermicide, condom with spermicide, or abstinence) for the duration of the study. 
 
Male subject agrees to use an acceptable method of contraception for the duration of the study. 
 
Age > 15years old and over 40 kg. Life expectancy of greater than 3 months. 
 
ECOG of 0-2.   
 
Patients must have normal organ and marrow function as defined below: 
o Total bilirubin within 1.5x the upper limit of normal institutional limits. Patients with elevation 
of unconjugated bilirubin alone, as in Gilbert’s disease, are eligible. 
o AST/ALT < 3.0x institutional upper limit of normal (unless demonstrated Hodgkin lymphoma 
involvement of the liver). Estimated creatinine clearance ≥30 ml/min (Cockcroft-Gault) and/or 
24 urine analysis as needed 
o PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN. 
 


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3.1.1 
Child Bearing Potential 
The effects of brentuximab vedotin and ibrutinib on the developing fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control or abstinence) prior to study entry and for six months following duration 
of study participation. Should a woman become pregnant or suspect that she is pregnant while 
participating on the trial, she should inform her treating physician immediately. 
3.1.2 
Informed Consent/Assent 
All subjects must have the ability to understand and the willingness to sign a written informed consent. 
They are to give voluntary written informed consent before performance of any study-related procedure 
not part of normal medical care, with the understanding that consent may be withdrawn by the subject 
at any time without prejudice to future medical care. 
3.1.3 
Prior Therapy 
 
Patient must be either refractory to or relapsed after 1 line of therapy.   
 
Prior radiation therapy is allowed.   
 
Prior hematopoietic transplantation is allowed (autologous and/or allogeneic) 
 
Prior brentuximab vedotin is allowed provided that patients were not refractory (defined as 
developing progressive disease while on treatment or progressed within 3 months of finished last 
dose of brentuximab vedotin) 
 
Prior ibrutinib for Hodgkin lymphoma is not allowed.  
3.2 Exclusion Criteria 
 
Age < 15 and less than or equal to 40 kg 
 
Prior ibrutinib for Hodgkin lymphoma is not allowed.  
 
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. 
 
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). 
 
Patients should not have any uncontrolled illness including ongoing or active infection. 
 
Patients may not be receiving any other investigational agents, or concurrent biological therapy, 
chemotherapy, or radiation therapy.   
 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
ibrutinib and BV. 
 
Patients must not have received prior chemotherapy or radiation for < 3 weeks before study enrollment, 
or those who have not recovered from the adverse events due to agents administered more than 3 weeks 
earlier are excluded.   
 
Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) 
Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to 
study entry, any ECG abnormality at screening has to be documented by the Investigator as not 
medically relevant. 
 
Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle 
branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval 


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(QTc) ≥470 msec. Subjects with a cardiac pacemaker who have a QTc interval of ≥470 msec may be 
eligible if these findings are considered not clinically significant as documented via a cardiology 
evaluation. 
 
Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of 
complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ 
malignancy, or low-risk prostate cancer after curative therapy.   
 
Patients with active CNS disease or history of brain metastases are excluded from study. 
 
Patients may be on steroids prior to initiation of treatment, provided that, by cycle 1 day 1, steroids use 
was tapered down to less than or equal to 20 mg of prednisone.  
 
Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient 
effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary 
to treatment of the mother, breastfeeding should be discontinued.  
 
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 
 
Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of 
study drug. 
 
Known active infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or 
hepatitis B virus (HBV). Testing to be done only in patients suspected of having infections or exposures. 
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. Subjects who have an undetectable HIV viral load with CD4 > 200 and are on HAART 
medication are allowed. 
 
Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the 
Child Pugh classification 
 
3.2.1 
Study-Specific Exclusions 
 
Patient has hypersensitivity to brentuximab vedotin  
 
Refractory to prior brentuximab vedotin (defined as developing progressive disease while on treatment 
or progressed within 3 month of finished last dose of brentuximab vedotin) 
 
Prior ibrutinib for Hodgkin lymphoma is not allowed.  
 
No active GVHD or on immunosuppressive medication for GVHD 
 
Recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the 
first dose of study drug 
 
Unresolved toxicities from prior anticancer therapy, defined as having not resolved to Common 
Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade 0 or 1, or to the levels dictated 
in the inclusion/exclusion criteria, with the exception of alopecia 
 
Baseline Grade II peripheral neuropathy 
 
Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia. 
 
History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
 
Major surgery within 4 weeks of first dose of study drug. 
 
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 
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 
Concomitant use of warfarin or other Vitamin K antagonists. 
 
Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor. (see Appendix 1) 
3.2.2 
Non-Compliance 
Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring 
requirements of the study. 
3.3 Inclusion of Women and Minorities 
The study is open to anyone regardless of gender or ethnicity. Efforts will be made to extend the accrual to 
a representative population, but in a trial which will accrue approximately 39 subjects, a balance must be 
struck between subject safety considerations and limitations on the number of individuals exposed to 
potentially toxic or ineffective treatments on the one hand and the need to explore gender, racial, and ethnic 
aspects of clinical research on the other. If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
4.0 
Participant Enrollment 
4.1 Screening , Informed Consent and Enrollment 
4.1.1 
Pre-Enrollment Informed Consent and Screening Procedures 
The investigational nature and objectives of the trial, the procedures and treatments involved, and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the subject, 
and a signed informed consent will be obtained. Documentation of informed consent for screening will be 
maintained in the subject’s research chart and medical record.   
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained.  
The informed consent process is to be fully documented (see Section 16.4), and the prospective participant 
must receive a copy of the signed informed consent document. Screening procedures are listed ins Section 
9.0. 
4.1.2 
Enrollment 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center (DCC) at City 
of Hope.  DCC staff is available between the hours of 8:00 a.m. and 5:00p.m. PST, Monday through 
Friday (except holidays).   DCC contact information is as follows: 
 
phone: (626) 218-7904 
 
e-mail: DCC@coh.org 
4.1.3 
Slot verification and reservation 
Issues that would cause treatment delays should be discussed with the Study PI. Designated study staff 
should call or email the DCC to verify current slot availability, and to reserve a slot for a specific prospective 
subject (provide DCC with subject initials).  Slots can only be held for a limited time. 
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible. 
4.1.4 
Registration Process 
To register a participant, the subsequent procedure is to be followed. 


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1. The study team should contact the DCC via telephone or email to provide notification 
regarding the pending registration and communicate desired timeline of the registration, 
especially if it must be completed promptly to meet the registration window. 
2. The protocol nurse or CRC should then e-mail a copy of the following documents to 
DCC@coh.org:  
o Registration Cover Sheet (non-COH sites only, see Appendix 7) 
o Completed Eligibility Criteria List (printed from Section 3.0 of the 
protocol) 
o Source documentation to support eligibility criteria**  
o Signed informed consent document 
o Signed HIPAA authorization form 
o Signed subject’s Bill of Rights 
**It is NOT acceptable to submit emails as source documentation. 
3. After having received all documentation, the DCC will complete the review the documents 
to verify eligibility, working with the study team as needed to resolve any missing required 
source elements. A participant failing to meet all protocol eligibility requirements will not 
be registered.  
4. Once eligibility is confirmed DCC staff will send a Confirmation of Registration Form, 
and signed Eligibility Checklist within 24 hours, including the participant study number 
and dose level assigned to:  
o the study team: site PI, treating physician, biostatistician, protocol nurse, 
CRC, and pharmacy. 
o the COH sponsor team designees. 
5. Upon receipt of the Confirmation of Registration email from the DCC, COH study team 
will register the patient in OnCore. DCC will register non-COH patients in OnCore. 
4.1.5 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC if the participant screen fails after registration or if the participant does not start 
treatment. 
4.2 Dose Level Assignment  
The Data Coordinating Center will be responsible for centrally registering all subjects for this trial and 
therefore will provide the participating site’s the specific information pertaining to the dose level for each 
patient. 
5.0 
Treatment Program 
5.1 Treatment Overview 
Treatment will be given on an outpatient basis unless patients are already hospitalized for symptoms of 
Hodgkin lymphoma.    
5.1.1 
Brentuximab vedotin Dose and Administration  
Brentuximab vedotin (BV): BV is an antibody-drug conjugate consisting of the anti-CD30 antibody cAC10 
conjugated to MMAE, an anti-tubulin agent. BV is a sterile, preservative-free, white to off-white 
lyophilized cake for reconstitution for IV administration. BV is supplied commercially in single-use, Type 


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1 borosilicate glass vials with FluroTec®-coated butyl rubber stoppers and aluminum seals. Each vial of the 
product contains BV, trehalose, sodium citrate, and polysorbate 80.  
BV will be administered on Day 1 of each 21-day cycle. The dose of BV is 1.8 mg/kg and is administered 
by outpatient IV infusion given over approximately 30 minutes until PD or unacceptable toxicity. In the 
absence of infusion toxicities, the infusion rate for all patients must be calculated in order to achieve a 30-
minute infusion period. BV must not be administered as an IV push or bolus. BV should be administered 
through a dedicated IV line. BV cannot be mixed with other medications.  
Dosing should be based on baseline weight; doses will be adjusted for patients who experience a ≥10% 
change in weight during the study. Actual weight will be used except for patients weighing greater than 
100 kg; dose will be calculated based on 100 kg for these individuals. BV dose should be rounded per 
institutional policy.  
5.1.2 
BV Required Premedication and Postmedication  
Routine premedication should be administered prior to the first dose of BV. Please see Section 5.1.3 below. 
Patients who experience a Grade 3 or Grade 4 infusion-related reaction may potentially receive additional 
treatment with BV at the discretion of the Investigator.  
5.1.3 
BV Management of Infusion Reactions  
Infusion-related reactions may occur during the infusion of BV. The infusion should be administered at a 
site properly equipped and staffed to manage anaphylaxis should it occur. The patient should be observed 
for 60 minutes following the first infusion of BV.  
During this observation period, the IV line should remain open for at least 1 hour to allow administration 
of IV drugs if necessary. All supportive measures consistent with optimal patient care will be given 
throughout the study according to institution standards. Medications for infusion-related reactions, such as 
epinephrine, antihistamines, and corticosteroids, should be available for immediate use.  
Premedications consist of acetaminophen (650 mg orally) and diphenhydramine (25–50 mg orally or 25–
50 mg IV),IV or oral pepcid 20-40 mg and hydrocortisone (maximum of 100 mg) administered 30–60 
minutes prior to each 30-minute BV infusion.  Premedication is required prior to each cycle of BV + IB.  
These medications may be given again as treatment of infusion related reactions.  The infusion of BV can 
also be slowed down to 60-90 minutes if patients has developed previous infusion reaction of any grade.   
5.1.4 
Ibrutinib (to be given prior to infusion with BV) 
5.1.4.1 Formulation/Packaging/Storage  
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 drugs will be 
dispensed in child-resistant packaging.   
Refer to the 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. 
5.1.5 
Dose and Administration  
In the lead in phase, an initial dose of ibrutinib 420 mg is given orally once daily.  Once that is proven to 
be safe, we will give 560 mg of ibrutinib orally daily.  In the phase II portion, Ibrutinib 560 mg (4 x 140-


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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 subjects 
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 (See 
Appendix 1).  
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 subject should not take extra capsules to make up the missed 
dose. A subject diary will be used to aid with as well as document study drug administration compliance. 
At any given visit, enough ibrutinib capsules to carry the subject to the next visit should be dispensed. 
Unused ibrutinib capsules dispensed during previous visits must be returned, and drug accountability 
records should be updated. Returned capsules must not be redispensed to anyone. Subjects should return 
all empty bottles to the site. Empty bottles should be destroyed at the site or returned to the Sponsor after 
the site monitor has completed a review of drug accountability 
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 subjects in bottles at each visit.   
5.1.6 
Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an overdose. Signs 
and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a Serious 
Adverse Event in the appropriate time frame and documented as clinical sequelae to an overdose. 
There is no specific experience in the management of ibrutinib overdose in patients. No MTD was reached 
in the phase 1 study in which subjects received up to 12.5 mg/kg/day (1400 mg). 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. 
5.1.7 
Schedule 
For a tabular view of the treatment, monitoring, and follow-up schedule, see study calendar in Section 9  
Each cycle is 21 days 
Ibrutinib 
Brentuximab Vedotin 
Dose level 1 
420 mg orally daily  
1.8 mg/kg IV every 3 weeks  
Dose level 2 
560 mg orally daily 
1.8 mg/kg IV every 3 weeks  
Brentuximab vedotin dosing can be given during a window of + 3 days due to scheduling issues.  
Prior to formally initiating the phase II trial, a patient safety lead-in segment will be conducted to ensure 
there are no unexpected toxicities during cycle 1. Ultimately a total of 39 patients will be treated at phase 
II  and evaluated for response at the ibrutinib/brentuximab vedotin doses considered safe -as determined 
during the safety lead-in segment of this study. 
The first nine to twelve patients enrolled will be part of the patient safety lead-in. Initially, a group of up to 
3 patients can be enrolled on dose level 1; given the potential for overlapping toxicity, the initial dose of 
ibrutinib tested will be 420 mg daily. During the safety lead-in, no more than 3 patients can be under active 
cycle 1 toxicity evaluation. Note: Unacceptable toxicity in a given patient is defined as any non-hematologic 
grade 3|4 toxicity or, for hematologic toxicities, any grade 3|4 that does not resolve to a grade 1|2 within 7 
days per NCI CTCAE v4.03 toxicity criteria and is considered at least possibly related to ibrutinib and/or 
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The safety lead-in segment will follow standard 3+3 dose escalation/de-escalation/expansion rules based 
on observed toxicity during cycle 1: (Note: Dose de-escalation, escalation or cohort expansion will only 
take place after 3 patients are fully assessed using the Common Terminology Criteria for Adverse Events 
(CTCAE) of the National Cancer Institute (NCI) version 4.03 following the completion of cycle 1.)  
• 
If 0 out of 3 evaluable patients experience unacceptable toxicity during cycle 1, then the next dose 
level of combination therapy will be tested. 
• 
If 1 out of 3 evaluable patients experience unacceptable toxicity during cycle 1, three additional 
patients will be assessed at the same dose level of combination therapy. 
• 
If 2 out of 3 evaluable patients experience unacceptable toxicity during cycle 1, dose escalation 
will cease and the next lower dose level of combination therapy will be expanded. Note: If 2 out of 3 
experience unacceptable toxicity on dose level 1, the trial will be stopped. Doses below 420mg 
(ibrutinib)/1.8mg/kg (brentuximab vedotin) will not be considered. 
• 
If 1 out of 6 evaluable patients experience unacceptable toxicity during cycle 1, then dose escalation 
to the next dose level of combination therapy will continue.  
• 
If 2 or more out of 6 evaluable patients experience unacceptable toxicity during cycle 1, dose 
escalation will cease and the next lower dose level of combination therapy will be expanded. Note: If 2 or 
more out of 6 experience unacceptable toxicity on dose level 1, the trial will be stopped. Doses below 
420mg (ibrutinib)/1.8mg/kg (brentuximab vedotin) will not be considered. 
The highest dose level that produces ≤1/6 evaluable patients with unacceptable toxicity during cycle 1 will 
be the declared safe dose and brought forward for phase II evaluation. 
5.2 Planned Duration of Therapy 
BV will be given intravenously once every 3 weeks, ibrutinib will be given daily. Each cycle is 21 days. 
Patients will be treated until disease progression, unacceptable toxicity, or moving onto autologous or 
allogeneic-HCT. The minimum number of cycles required prior to discontinuation should be 4, unless the 
patient developed progressive disease or intolerable AEs. For patients who achieve CR/PR and then relapse 
while off treatment (for toxicities, auto-HCT, or allo-HCT), they can receive additional cycles of treatment. 
There will be no maximum cycles of treatment for patients at retreatment. There is no limit on the number 
of times patients can be retreated. For patients who ultimately undergo autologous or allogeneic-HCT and 
then relapse post transplant, these patients will be allowed to re-enter the study. 
5.3 Criteria for Removal from Treatment 
Disease progression, intolerable AEs, non-compliance, or patient withdraws consent.  
5.4 Subject Follow-Up 
Patients will be followed for the duration of active treatment per treatment visit. After treatment, subjects 
will be followed for up to two years with q3 month interval visits or telephone calls.  For patients who 
undergo autologous or allogeneic HCT, patients will be followed for up to two years with q3 months interval 
visits or phone calls post HCT.   
5.5 Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Use of neutrophil growth factors or biosimilars is permitted per institutional policy and the American 
Society of Clinical Oncology (ASCO) guidelines. Transfusions may be given in accordance with 
institutional policy. 
 
Any medications known to cause QT prolongation should be used with caution; periodic ECG and 
electrolyte monitoring should be considered. 


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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. For subjects requiring the initiation of therapeutic anticoagulation 
therapy (e.g. 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. 
 
Chemotherapy, anticancer immunotherapy, corticosteroids for cancer-related reasons (at doses equivalent 
to prednisone >20 mg/day for >14 days), experimental anticancer therapy, or radiotherapy are prohibited 
while the subject is receiving ibrutinib and brentuximab vedotin. Corticosteroids for the treatment of non-
cancer-related reasons for longer than 14 days and/or at doses >100 mg/day of prednisone or its equivalent 
are also prohibited. 
 
Ibrutinib may increase the risk of bleeding with invasive procedures or surgery. The following guidance 
should be applied during the perioperative period for subjects who require surgical intervention or an 
invasive procedure while receiving ibrutinib: 
 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 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. 
 
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. 
 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is reasonably 
healed and for at least 7 days after the urgent surgical procedure.  
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A inhibitor (eg, 
ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, and 
nefazadone) or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If 
a strong CYP3A inhibitor must be used, either reduce ibrutinib dose to 140 mg or withhold treatment 
temporarily. Subjects should be monitored for signs of ibrutinib toxicity. If a moderate CYP3A inhibitor 
must be used, reduce ibrutinib to 140mg for the duration of the inhibitor use. No dose adjustment is required 
in combination with mild inhibitors. Avoid grapefruit and Seville oranges during ibrutinib treatment, as 
these contain moderate inhibitors of CYP3A (see Appendix 1). 
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 1.  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. 


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For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please refer to 
the current version of the IB. 
Ibrutinib may be associated with opportunistic infections, therefore it is recommended but not required that 
patients be placed on antibiotic prophylaxis per institutional standards such as (acyclovir for VZV 
reactivation or bactrim for PCP prophylaxis) 
6.0 
Dose Modification for Adverse Events 
6.1 Anticipated Toxicities 
6.1.1 
Ibrutininb  
Per the package insert (January 2019) the expected toxicities for ibrutinib are as follows: 
System Organ Class 
Adverse Reactions 
Gastrointestinal disorders 
 
Very common 
Nausea, diarrhea, vomiting, constipation, 
abdominal pain, stomatitis, dyspepsia 
 
Frequency not known 
Gastrointestinal esophageal reflux disease 
Infections and infestations  
 
Very common 
Infectiona, upper respiratory tract infection, 
sinusitis, pneumonia, urinary tract infection, skin 
infection 
 
Frequency not known 
Hepatitis B reactivation 
Blood and lymphatic system disorders 
 
Very common 
Neutropenia, thrombocytopenia  
 
Common 
anemia 
Cardiac disorders 
 
Very Common 
Ventricular tachyarrythmiasa 
 
Common 
Atrial fibrillation 
Immune system disorders 
 
Frequency not known 
Anaphylactic reaction, angioedema, urticaria 
Metabolism and nutrition disorders 
 
Common 
Decreased appetite, dehydration, 
hypoalbuminemia, hypokalemia, hyperuricemia 
 
Frequency not known 
Tumor lysis syndrome 
Nervous system disorders 
 
Very common 
Dizziness, headache 
 
Frequency not known 
Peripheral neuropathy 
Respiratory, thoracic and mediastinal disorders 
 
Very common 
Cough, dyspnea, epistaxis, oropharyngeal pain 
 
Frequency not known 
Interstitial lung diseasea 
Hepatobiliary disorders 
 
Frequency not known 
Acute hepatic failure, hepatic cirrhosis 
Eye disorders 


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System Organ Class 
Adverse Reactions 
 
Very common 
Blurred vision 
Skin and subcutaneous tissue disorders 
 
Very common 
Rasha, pruritus, bruising, petechiae 
 
Frequency not known 
Stevens-Johnson syndrome, panniculitis, 
onychoclasis 
Musculoskeletal and connective tissue disorders 
 
Very common 
Musculoskeletal paina, myalgia, muscle spasms 
Neoplasms, benign malignant and unspecified 
 
Very common 
Secondary malignancy 
General disorders and administration site conditions 
 
Very common 
Fatigue, pyrexia, peripheral edema, asthenia, chills 
Vascular disorders 
 
Very common 
Hypertension, hemorrhagea 
Investigations 
 
Very common 
Weight decreased 
a Represents pooling of preferred terms 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 
to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). 
Refer also to Section 2.4.2. 
6.1.2 
Brentuximab Vedotin  
Per the IB (version 16, October 2018) the expected toxicities for brentuximab vedotin are as follows: 
System Organ Class 
Adverse Reactions 
Infections and infestations  
 
Very common 
Infectiona, upper respiratory tract infection 
 
Common 
Herpes zoster, pneumonia, herpes simplex, oral candidiasis 
 
Uncommon 
Pneumocystis jiroveci pneumonia, staphylococcal 
bacteremia, cytomegalovirus infection or reactivation, 
sepsis/septic shock 
 
Frequency not known 
Progressive multifocal leukoencephalopathy 
Blood and lymphatic system disorders 
 
Very common 
Neutropenia 
 
Common 
Anemia, thrombocytopenia 
 
Uncommon 
Febrile neutropenia 
Immune system disorders 
 
Uncommon 
Anaphylactic reaction 
Metabolism and nutrition disorders 
 
Common 
Hyperglycemia 
 
Uncommon 
Tumor lysis syndrome 
Nervous system disorders 
 
Very common 
Peripheral sensory neuropathy, peripheral motor neuropathy 


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System Organ Class 
Adverse Reactions 
 
Common 
Dizziness 
 
Uncommon 
Demyelinating polyneuropathy 
Respiratory, thoracic and mediastinal disorders 
 
Very common 
Cough, dyspnea 
Gastro-intestinal disorders 
 
Very common 
Nausea, diarrhea, vomiting, constipation, abdominal pain 
 
Uncommon 
Pancreatitis acute 
Hepatobiliary disorders 
 
Common 
Alanine aminotransferase/aspartate aminotransferase 
increased 
Skin and subcutaneous tissue disorders 
 
Very common 
Rasha, pruritus 
 
Common 
Alopecia 
 
Uncommon 
Stevens-Johnson syndrome/toxic epidermal necrolysis 
Musculoskeletal and connective tissue disorders 
 
Very common 
Arthralgia, myalgia 
 
Common 
Back pain 
General disorders and administration site conditions 
 
Very common 
Fatigue, pyrexia, infusion-related reactionsa 
 
Common 
Chills 
Investigations 
 
Very common 
Weight decreased 
a Represents pooling of preferred terms 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 
to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). 
6.2 Dose Modifications 
Given that brentuximab vedotin has demonstrated activity in this disease setting, ibrutinib should be 
preferentially dose reduced in the event of toxicity. The only exception is in the event of peripheral 
motor or sensory neuropathy, in that case, brentuximab vedotin dose will be reduced 1st given its 
direct correlation to brentuximab vedotin.   
Ibrutinib (supplied by Pharmacyclics): 
Interrupt or discontinue therapy 
 Interrupt therapy for any non-hematological toxicity ≥Grade 3, neutropenia with infection or fever 
≥Grade 3, or Grade 4 hematological toxicities 
 Reinitiate ibrutinib at the starting dose (indicated specific) once toxicities have resolved to Grade 1 
or baseline (recovery) 
 If the toxicity reoccurs, reduce dose by 1 capsule (140 mg/day) 
 A second reduction of dose by 140 mg may be considered as needed 
 Discontinue if these toxicities persist or recur following 2 dose reductions 
Hepatic impairment 
 Mild (Child Pugh class A): 140 mg PO qDay 
 Moderate-to-severe (Child Pugh Classes B and C): Avoid use 


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Brentuximab vedotin and Ibrutinib: 
If either agent were held for toxicities, the next cycle of treatment will be delayed until toxicities become 
acceptable for both drugs before treatment continues.  Both drugs will be given at the start of each cycle.  
For example, if brentuximab vedotin was dose delayed for peripheral neuropathy for 4 weeks, Ibrutinib 
dosing will stop after 3 weeks and held.  Ibrutinib will be given again when it is deemed acceptable to start 
brentuximab vedotin.  If Ibrutinib was held for thrombocytopenia at D15 and can be resumed at D18, 
brentuximab vedotin can be given at the original scheduled infusion day.  However, if ibrutinib was held at 
D15 and cannot resume for 2 weeks later, then brentuximab vedotin will only be given at the same time 
Ibrutinib is restarted.   
Brentuximab vedotin (commercial supply): 
Peripheral Neuropathy:  Peripheral neuropathy should be managed using a combination of dose delay 
and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until 
neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral 
neuropathy, BV should be discontinued. 
Neutropenia:  Neutropenia should be managed by dose delays and reductions. For grade 1 or 2, continue 
at same dose. The dose of BV should be held for Grade 3 or 4 neutropenia until resolution to baseline or 
Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who 
experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of 
growth factors, and despite dose reduction specified for ibrutinb, discontinuation or dose reduction of BV 
to 1.2 mg/kg may be considered.   
Anemia and thrombocytopenia: For Grade 1 or 2, continue at same dose. For Grade 3 and 4, withhold 
dose until toxicity is < Grade 2 or has returned to baseline, then resume treatment at the same dose level. 
For second occurrence of Grade 4, withhold until toxicity < Grade 1 or has returned to baseline, then resume 
treatment at 1.8 mg/kg but reduce ibrutinib dose from 560 mg to 420 mg.  For third occurrence, withhold 
until toxicity < grade 1 or has returned to basleine, then resume BV at 1.8 mg/kg but reduce ibrutinib dose 
from 420 mg to 280 mg.  In patients with recurrent grade 4 anemia and thrombocytopenia despite dose 
reduction specified for ibrutinib, then resume treatment of BV at 1.2 mg/kg. If patient was already at 1.2 
mg/kg of BV, then discontinue treatment of BV and ibrutinib.  
Other non-hematological toxicities: For Grade 1 or 2, continue at same dose. For Grade 3, withhold dose 
until toxicity is < Grade 1 or has returned to baseline, then resume treatment at the same dose level. For 
Grade 4, withhold until toxicity < Grade 1 or has returned to baseline, then resume treatment at same dose 
level but reduce ibrutinib dose from 560 mg to 420 mg.  For second occurrence of Grade 3, withhold dose 
until toxicity < Grade 1 or has returned to baseline, then resume BV at same dose level, but reduce ibrutinib 
from 560 mg to 420 mg.  For second occurrence of Grade 4, withhold until toxicity < Grade 1 or has 
returned to baseline, then resume BV at same dose level but reduce ibrutinib from 420 mg to 280 mg.  For 
third occurrence of Grade 3, withhold dose until toxicity < Grade 1 or has returned to baseline, then resume 
BV at same dose level but reduce ibrutinib from 420 mg to 280 mg.  For third occurrence of grade 4 toxicity, 
discontinue ibrutinib.  In patients with recurrent grade 3 and 4 non hematological toxicities despite dose 
reduction specified for ibrutinib, then reduce treatment of BV to 1.2 mg/kg. If patient was already at 1.2 
mg/kg of BV, then discontinue treatment of BV and ibrutinib. 
The start of the next cycle may be delayed for up to 3 weeks if additional time is required for the patient to 
recover from study treatment-associated toxicity experienced during the current cycle. Delays of greater 
than 3 weeks are prohibited without approval of the PI.  


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Doses reduced for drug-related toxicity should generally not be re-escalated. However, intra-patient re-
escalation to the previous dose level may be permitted at the discretion of the PI.   
 
7.0 
Agent Information and Risks 
7.1 7.1 Brentuximab vedotin 
7.1.1 
Description 
Brentuximab vedotin (BV), is also named SGN-35, or Adcetris. BV is an antibody-drug conjugate 
consisting of the anti-CD30 antibody cAC10 conjugated to MMAE, an anti-tubulin agent. BV is a sterile, 
preservative-free, white to off-white lyophilized cake for reconstitution for IV administration. It is 
supplied by Seattle Genetics in single-use, Type 1 borosilicate glass vials with FluroTec®-coated butyl 
rubber stoppers and aluminum seals. Each vial of the product contains BV, trehalose, sodium citrate, and 
polysorbate 80.  
7.1.2 
Toxicology 
The toxicity of multiple doses of brentuximab vedotin has been assessed in rats and monkeys. In both 
species, hypocellularity of the bone marrow and lymphoid depletion of the thymus were observed. 
Histopathologic lesions were also observed in the spleen in monkeys and in the liver and testes in rats. In 
addition, decreases in peripheral blood counts were observed in both species, and elevations in liver 
enzymes were seen in rats only. The most significant clinical toxicity was neutropenia, observed in 
monkeys, which resulted in secondary bacterial infections leading to early deaths at the 6 mg/kg dose. 
Toxicity was dose-dependent, with a no-observable-adverse-effect level of 0.5 mg/kg in rats and 1 mg/kg 
in monkeys. See the brentuximab vedotin SGN-35 Investigator’s Brochure for details of the toxicology 
data. 
7.1.3 
Pharmacology – Handling, Storage, Dispensing and Disposal 
BV will be from a commercial supply. Please see package insert for dose preparation and storage 
information. 
7.2 Ibrutinib 
7.2.1 
Description 
Ibutinib is also named Imbruvica. It is an inhibitor of Bruton’s tyrosine kinase. It is a small molecule with 
the molecular formula C25H24N6O2 and a molecular weight of 440.5. Ibrutinib capsules for oral 
administration are supplied as gray opaque capsules that contain 140 mg ibrutinib as the active ingredient. 
The inactive ingredients are croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and 
sodium lauryl sulfate. 
 
Figure 1. Ibrutinib 


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7.2.2 
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.   
On the basis of data from rats and dogs, 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 daily doses of 420 and 560 mg, respectively. 
7.2.3 
Pharmacology-Handling, Storage, Dispensing, and 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 of the study drug will 
be dispensed in child-resistant packaging.   
Refer to product label for additional guidance on study drug storage, preparation dispensing, handling and 
disposal. 
8.0 
Correlative/Special Studies 
Each subject will have either a fresh core or excisional biopsy of a tumor lesion prior to starting study 
therapy or will have available archival tissue from a biopsy that was performed after the most recent 
therapy and within 3 months of the screening date. If feasible, all subjects will also undergo biopsy of a 
tumor lesion at the time of disease progression. 
Guidelines for tumor sampling are as follows: 
 
For fresh biopsies: 
a. For core biopsies, 2 core biopsy tumor samples will be immediately frozen and processed  
b. For excisional biopsies, an approximately 5mm x 5mm tumor sample will be immediately 
frozen and processed 
c. The remainder of the specimen will be processed in a routine fashion by hematopathology. 
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples 
will be processed for correlative studies: 
i. 10 x 5 micron paraffin slices 
ii. 10 x 5 micron unstained slides 
 
Fresh or frozen tissue from excisional biopsies or 2-3 needle cores will be minced into smaller 
fragments. Using a lysis buffer, the nuclei will be released and isolated using a gradient solution. 
The pelleted nuclei will then be stained with DAPI and sorted by flow cytometry by DNA 
content/ploidy at the City of Hope Cytometry Core. The supernatant from the gradient, which 


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contains the cytoplasmic contents of the Hodgkin cells and inflammatory background cells, will 
be saved for RNA extraction. DNA will be extracted from the Hodgkin nuclei as well as 
normal/diploid, and the paired samples will be evaluated by whole exome sequencing.   
 
FFPE tissue blocks will be examined for CD30 expression, drug exporter expression, and CD68 
tumor macrophages. We will also isolate DNA/RNA from inflammatory cells in the 
microenvironment and perform gene expression profiling signatures.  
 
We will also obtain tumor biopsies from patients who develop progressive disease while on 
treatment. We will test for CD30 and drug exporter expression by immunohistocytochemistry and 
will compare with the pre-treatment sample. We will also perform gene expression profiling on 
post-treatment relapse samples and compare with pre-treatment samples.   
 
For archival specimens: 
a. Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples 
will be processed for correlative studies: 
i.  10 x 5 micron paraffin slices 
ii. 10 x 5 micron unstained slides 
For non COH sites refer to Appendix 3 for tissue shipping guidelines. 
 
For peripheral blood collections: 
a. 36 ml of peripheral blood will be drawn on day 1 prior to dosing, day 8 during cycle 1, and 
on day 1 cycle 2 prior to dosing.  They will be analyzed for: 
i. T/B/NK cell subsets.  20 ml of blood will be drawn in sodium heparin tube.  They 
will be sent to Dr. Peter Lee’s lab at COH.  8-color flow cytometric analysis will 
be performed to phenotype immune cell subsets and functional readouts.  A 
prototype BD microfluidic FACS instrument that can analyze small cell numbers 
will be used. Markers to be assessed: TIGIT, PD-1, CD45, CD4, CD8, CD103, 
CD69, and CCR7.  BTK and ITK occupancy will also be evaluated Leftover blood 
to be processed into viable cryopreserved PBMCs and stored for future analysis. 
For non COH sites, refer to Appendix 5 for blood shipping guidelines.    
ii. ITK and BTK occupancy will be assessed by Pharmacyclics.  See Appendix 2 for 
instructions. 2 x 8 ml CPT citrate tube whole blood (PBMC and plasma) to support 
BTK/ITK occupancy and optional retrospective cytokine/chemokine testing at 
PCYC.    


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9.0 
Study Calendar 
 
Pre-Study 
(within 28 
days) 
Cycle 1 
Cycle 2 and beyond 
(Each cycle 3 weeks) 
Off Study Visit 
Wk
1 
Wk 2 
+/- 1 
day 
Wk3 
+/- 1 
day 
Wk1 
Wk2 
Wk3 
BV 
 
X 
 
 
x 
 
 
 
Ibrutinib 
 
X 
X 
X 
x 
x 
x 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
X 
Concurrent meds 
X 
 
 
 
x 
 
 
X 
Physical exam 
X 
X 
 
 
x 
 
 
X 
Vital signs 
X 
X 
 
 
x 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
x 
 
 
X 
Performance Status 
X 
X 
 
 
x 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
X 
x 
 
 
X 
Serum chemistrya 
X 
X 
X 
X 
x 
 
 
X 
PT/PTT/INR 
X 
 
 
 
x 
 
 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
 
 
X 
Tumor measurements 
X 
 
 
 
Xb 
 
Radiologic evaluation 
X 
 
 
 
Xc 
 
B-HCG 
X 
 
 
 
 
 
 
 
Tissue for correlative studiesd 
X 
 
 
 
 
 
 
X 
Peripheral blood for correlative 
studiese  
 
X 
X 
 
X 
 
 
 
a. Serum chemistry includes (comprehensive metabolic profile: sodium, potassium, chloride, carbon 
dioxide, glucose, blood urea nitrogen, creatinine, AST, ALT, Alkaline phosphate, total bilirubin, 
calcium, albumin, total protein, magnesium, phosphate). 
b. Tumor measurements to be done at end of C2 (+/- 7 days), C4 (+/- 7 days),, C7 (+/- 7 days),, and 
every 3 cycles until patients achieves CR.  Once CR documented twice by CT scan, intervals can be 
increased to q6 cycles while patient is still on study drug.  If patient comes off study, CT scan will 
only be performed q6 month for 2 years and no protocol scans will be done 2 years post treatment.  
c. CT/PET to be done at C4 (+/- 7 days),, C10 (+/- 7 days),, and q 6 cycles until patient achieves CR.  
However, once CT/PET is negative, only CT scan need to be done after that, PET can be avoided. 
d. Each subject will have either a fresh core or excisional biopsy of a tumor lesion prior to starting 
study therapy or will have available archival tissue from a biopsy that was performed after the most 
recent therapy and within 3 months of the screening date. If feasible, all subjects will also undergo 
biopsy of a tumor lesion at the time of disease progression. Refer to Section 8 for details. 
e. Peripheral blood for correlative studies to be collected prior to cycle 1, day 8 of cycle 1, and day 1 of 
cycle 2 prior to treatment. Refer to Section 8 for details.   


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10.0 
Endpoint Evaluation Criteria/Measurement of Effect 
10.1 Definitions 
Evaluable for toxicity: All participants will be evaluable for toxicity from the time of their first treatment 
with ibrutinib plus brentuximab vedotin. 
Evaluable for objective response: Only those participants who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These participants will have their response classified according to the 
definitions stated below. 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR, per Cheson criteria24, (whichever is first recorded) until the first date that 
relapsed or progressive disease is objectively documented. 
Duration of overall CR: The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, per Cheson criteria24, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
Overall Survival (OS): OS is defined as the duration of time from start of treatment to time of death (due 
to any cause). 
Progression-Free Survival (PFS): PFS is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. 
10.2 Transplant Endpoint Definitions 
Overall Survival (OS): OS is defined as the duration of time from start of HCT treatment to time of death 
(due to any cause). Evaluated and recorded at day 30, day 100, 6 months, 1-year and 2-years post HCT. 
Progression-Free Survival (PFS): PFS is defined as the duration of time from start of HCT treatment to 
time of progression or death, whichever occurs first. Evaluated and recorded at day 30, day 100, 6 months, 
1-year and 2-years post HCT. 
Relapse/Progression (CIR): The event is relapse/progression. The time to this event is measured from 
start of HCT treatment. Deaths without relapse/progression are considered a competing risk. Surviving 
patients with no history of relapse/progression are censored at time of last follow-up. Evaluated and 
recorded at day 30, day 100, 6 months, 1-year and 2-years post HCT. 
Non-relapse mortality (NRM): NRM is defined as death occurring in a patient from causes other than 
relapse or progression. NRM is measured from start of treatment until non-disease related death, or last 
follow-up, whichever comes first. Deaths from relapse/progression are considered a competing risk. 
Evaluated and recorded at day 30, day 100, 6 months, 1-year and 2-years post HCT. 
Stem cell mobilization:  mobilization regimen used, median number of cells collected, median number of 
days to reach minimum collection.  
Engraftment (Recovery of Granulopoiesis and Megakaryopoiesis): Engraftment will be assessed using 
three distinct milestones: 1) (Autologous and Allogeneic) ANC (neutrophils) 0.5 x103/L achieved and 
sustained for 3 consecutive lab values on different days with no subsequent decline; 2) (Autologous) 
Platelets (PLT)  20 K/L independent of platelet transfusion support; and 3) (Allogeneic) PLT  25 K/L 


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independent of platelet transfusion support. For platelet recovery, date should reflect no transfusions in 
previous 3 days and the first of 3 consecutive lab values on different days. 
10.3  Response Criteria and Methods for Evaluation of Measurable Disease 
Diagnostic quality CT of the neck, chest, abdomen, and pelvis (N/C/A/P) will be performed at the end of 
Cycles 2, 7, 10, 13, and 16, and every 3 months after. PET-CT scans will be performed at end of Cycles 4, 
10, and 16. Once PET-CT is negative, it does not need to be performed again. If CT/PET remains positive 
at the end of Cycle 4 and CT/PET scan to be performed at cycle 10 and 16, dedicated CT does not need to 
be performed at end of cycle 10 or 16. MRI may be performed at the Investigator’s discretion for lesions 
not well-visualized by CT.  
The determination of anti-tumor efficacy will be based on objective response assessments made according 
to the Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2014)24 and treatment decisions 
by the investigator will be based on these assessments. Clinical response of progressive disease (PD), stable 
disease (SD), partial remission (PR), or complete remission (CR) will be determined at each assessment. 
Selection of up to 6 of the largest dominant nodes or nodal masses to follow for response assessment must 
be PET FDG-avid at baseline. Investigator evaluation of baseline radiographic assessment will enable study 
enrollment per Inclusion Criteria based on the presence of measurable disease > 1.5 cm evidenced by CT 
scan of the neck/chest/abdomen/pelvis or CT/PET scans. In addition, per the Revised Response Criteria for 
Malignant Lymphoma, these nodes or masses should be selected according to all of the following: they 
should be clearly measurable in at least 2 perpendicular dimensions; if possible, they should be from 
disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved.  
If the bone marrow was positive at baseline, a follow-up bone marrow aspirate and biopsy is required and 
must be negative for assessment of a CR. If the follow-up morphology is indeterminate, the biopsy tissue 
must be negative by immunohistochemistry or the patient will be assessed as a PR. 
 
11.0 
Statistical Considerations  
11.1 
Study Design 
11.1.1 Phase II 
The primary hypothesis: in patients with relapsed/refractory Hodgkin Lymphoma (HL), the two agent 
regimen combination of ibrutinib and brentuximab vedotin (BV) can increase the complete response (CR) 
rate. 
In a multi-center phase II trial investigating the use of single agent BV in relapsed/refractory HL patients 
post-AHCT, the overall response rate was 75%, the CR rate was 34%.2 Although single agent BV therapy 
is associated with a high overall response rate and tolerable toxicity, the CR rate and the duration of 
response can be improved. 
This multi-center, single arm phase II trial will implement a Simon Two-Stage Minimax Design (Simon 
1989; Jung 2004) to evaluate the antitumor activity of the two agent combination ibrutinib and brentuximab 
vedotin, as assessed by complete response (CR) rate, in patients with relapsed/refractory Hodgkin 
lymphoma. The study is expected to enroll a minimum of 19 and a maximum of 39 patients. The sample 
size is based on the desire to discriminate a promising CR rate of 50% from a disappointing response rate 
of 30% using a type I error rate of 0.05 and power of 80%.  
At stage 1, 19 patients will be entered on the study. If ≤ 6 complete responses are seen, the study will be 
terminated. If at least 7 patients achieve a complete response, the trial will continue to the second stage.  


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At stage 2, 20 additional patients will be entered. At the end of stage 2, if 17 or more patients experience a 
complete response, the combination will be considered worthy of further study. If ≤ 16 patients experience 
a complete response then no further investigation of the combination is warranted. 
11.1.2  Safety Lead-In 
Prior to formally initiating the phase II trial, a patient safety lead-in segment will be conducted to ensure 
there are no unexpected toxicities during cycle 1. Ultimately a total of 39 patients will be treated and 
evaluated for response at the ibrutinib/brentuximab vedotin doses considered safe -as determined during 
the safety lead-in segment of this study. 
The first nine to twelve patients enrolled will be part of the patient safety lead-in. Initially, a group of up to 
3 patients can be enrolled on dose level 1; given the potential for overlapping toxicity, the initial dose of 
ibrutinib tested will be 420 mg daily. During the safety lead-in, no more than 3 patients can be under active 
cycle 1 toxicity evaluation. . Note: Unacceptable toxicity in a given patient is defined as any non-
hematologic grade 3|4 toxicity or, for hematologic toxicities, any grade 3|4 that does not resolve to a grade 
1|2 within 7 days per NCI CTCAE v4.03 toxicity criteria and is considered at least possibly related to 
ibrutinib and/or brentuximab vedotin, or any other regimen-related cause of death.  
The safety lead-in segment will follow standard 3+3 dose escalation/de-escalation/expansion rules based 
on observed toxicity during cycle 1: (Note: Dose de-escalation, escalation or cohort expansion will only 
take place after 3 patients are fully assessed using the Common Terminology Criteria for Adverse Events 
(CTCAE) of the National Cancer Institute (NCI) version 4.03 following the completion of cycle 1.)  
• 
If 0 out of 3 evaluable patients experience unacceptable toxicity during cycle 1, then the next dose 
level of combination therapy will be tested. 
• 
If 1 out of 3 evaluable patients experience unacceptable toxicity during cycle 1, three additional 
patients will be assessed at the same dose level of combination therapy. 
• 
If 2 out of 3 evaluable patients experience unacceptable toxicity during cycle 1, dose escalation 
will cease and the next lower dose level of combination therapy will be expanded. Note: If 2 out of 3 
experience unacceptable toxicity on dose level 1, the trial will be stopped. Doses below 420mg 
(ibrutinib)/1.8mg/kg (brentuximab vedotin) will not be considered. 
• 
If 1 out of 6 evaluable patients experience unacceptable toxicity during cycle 1, then dose escalation 
to the next dose level of combination therapy will continue.  
• 
If 2 or more out of 6 evaluable patients experience unacceptable toxicity during cycle 1, dose 
escalation will cease and the next lower dose level of combination therapy will be expanded. Note: If 2 or 
more out of 6 experience unacceptable toxicity on dose level 1, the trial will be stopped. Doses below 420 
mg (ibrutinib)/1.8mg/kg (brentuximab vedotin) will not be considered. 
The highest dose level that produces ≤1/6 evaluable patients with unacceptable toxicity during cycle 1 will 
be the declared safe dose and brought forward for phase II evaluation. 
11.2 
Sample Size Accrual Rate 
Assuming 1) the ibrutinib 560 mg and brentuximab vedotin 1.8mg/kg doses are well tolerated and 2) the 
study does not close for futility, 39 evaluable participants (received at least 1 cycle of treatment) will be 
enrolled on the phase II portion of the study. Study enrollment will be complete within 24 months from 
activation (accrual of 1-2 participants per month). Note: Expected accrual for the safety lead-in segment: 
n=9.  


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11.3 
Safety Analysis and Stopping Rules for Excessive Toxicity 
Following the patient safety lead-in segment, the early stopping rule for safety/toxicity will continue to be 
assessed for each patient after cycle 1. The expected rate of unacceptable toxicity should not be ≥33%. See 
section 5.1.7 for unacceptable toxicity definition. This rule is in addition to the quarterly review of all 
toxicities submitted to the COH DSMC. Given the number of patients treated, if the unacceptable toxicity 
rate is ≥33%, patient accrual will be halted and a full review of the data by the Data Safety Monitoring 
Committee (DSMC) will be mandated. 
11.4 
Statistical Analysis Plan 
In general, data will be summarized by using counts and percents for discrete parameters, and by descriptive 
statistics (number of observations, mean, standard deviation, median, minimum and maximum) for 
continuous parameters. The complete response rate will be calculated as the percent of evaluable patients 
that have confirmed CR; exact 95% confidence intervals will be calculated for this estimate. Observed 
toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time 
of onset, duration, probable association with the study regimen and reversibility or outcome. Baseline 
information (e.g. the extent of prior therapy) and demographic information will be presented as well to 
describe the patients treated in this study. Time to response and survival endpoints will be estimated using 
the product-limit method of Kaplan and Meier. The cumulative incidence of relapse/progression and non-
relapse mortality will be calculated as competing risks. 
11.5 
Analysis of Correlative Endpoints:   
Because of the limited sample size inherent to phase II studies, the analysis of correlative endpoints is 
primarily exploratory. Standard descriptive methods will be used to summarize: 1) the role of CD30, CD68, 
and drug exporters on lymphoma specimens and 2) the role of T/B/NK cell subsets and BTK and ITK 
occupancy in the peripheral blood. If the combination is not found to have sufficient activity, these patterns 
may help explain the lack of activity. If sufficient activity is found, then participants who experience an 
objective response will be compared to those who did not in terms of correlates.  Estimates of variation will 
also prove useful for future clinical research on this regimen.  Formal testing of these comparisons is not 
planned.  All analysis will clearly document the exploratory nature of these studies, although no attempt 
will be made to adjust for multiple comparisons inherent in correlative studies. 
12.0 
Data Handling, Data Management, Record Keeping  
12.1 Source Documents  
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial.  
The Site Investigator or their designee will prepare and maintain adequate and accurate source documents.  
These documents are designed to record all observations and other pertinent data for each patient enrolled 
in this clinical trial.  Source documents must be adequate to reconstruct all data transcribed onto the case 
report forms. 
12.2 Data Capture Methods and Management 
Data for this trial will be collected using Medidata RAVE, City of Hope’s electronic capture system. 
Medidata RAVE is a web based, password protected system that is fully compliant with global regulatory 
requirements, including 21CRF Part 11 compliant.  
Study personnel at each site will enter data from source documents corresponding to a subject’s visit into 
the protocol-specific electronic Case Report Form (eCRF).  A system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, tracked, 


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and resolved through the EDC system directly. The study database will be updated in accordance with the 
resolved queries.  All changes to the study database will be documented. 
The Data Coordinating Center will run monthly data expectation reports that will list any outstanding and 
overdue data. The Data Coordinating Center will send via email to the participating site a report monthly 
on any missing and/or overdue data forms.  The participating site will be required to complete the missing 
and/or overdue data forms within 1 week of receipt of the report. 
Query reports will be generated on a monthly basis by the Data Coordinating Center. The Data 
Coordinating Center will send via email to the participating site a report monthly on any outstanding 
queries.   
The participating site staff (whether Principal Investigator or the staff collecting data at site) are required 
to take an eLearning Module within Medidata RAVE in order to obtain full access. The participating site 
staff will receive training via teleconference by COH DCC staff to review eCRFs that are specific to this 
protocol.  Continuous training will be offered to participating sites if any amendments affect changes to 
the eCRFs during the course of the trial. The eCRFs within Medidata RAVE for this trial will have 
detailed instructions in the form of Help Text that provide instructions for completing each required field 
on each form. 
12.3 Case Report Forms/Data Submission Schedule 
Study personnel at each site will enter data from source documents corresponding to a subject’s visit into 
the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that visit 
is available.  
The Investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the Investigator.  All case report forms must be completed by designated study personnel.  The completed 
case report forms must be reviewed, signed and dated by the Site Investigator or designee in a timely 
fashion. 
All data will be collected using electronic data collection system described in Section 12.2, and will be 
submitted according to the timelines indicated in Table 12.3.1. 
All data will be collected within 1-2 weeks using standard Medidata Electronic Data Capture (EDC) case 
report forms. Data will be collected and stored on secure computers as indicated in 12.2. After 2 years, we 
will access the COH CIBMTR data repository to retrieve data regarding post-HCT long-term outcomes 
through study termination. 
 
Table 12.3.1 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration 
On Study Forms 
Within 10 business days of registration 
Baseline Assessment Forms 
Within 10 business days of registration 
Treatment Forms 
Within 10 business days of treatment administration 
Adverse Event Report Forms 
Within 5 business days 
For transplant patients: within 10 business days of the end 
of evaluation period. 
Response Assessment Forms 
Within 10 business days of response assessment 


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Other assessment forms (e.g. 
concomitant meds, transplant data 
including mobilization, etc.) 
Within 10 business days of the assessment 
Transplant Core Intake Form 
Within 10 business days of stem cell infusion 
Post Transplant Disease Assessment 
Form 
Within 14 days of the end of evaluation period 
Off Treatment/Off Study Forms 
Within 10 business days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Forms 
Within 10 business days of the protocol defined follow up 
visit date or call 
 
12.4 Regulatory Records  
The Investigator will maintain records, including updating records in accordance with Good Clinical 
Practice guidelines and FDA regulations. Additional information regarding required documents is 
provided in the DCC Operations Manual, a supplement to this protocol. 
13.0 
Adverse Events and Unanticipated Problems 
13.1  Definitions  
13.1.1 Adverse Event (AE) 
An adverse event is any untoward medical experience or change of an existing condition that occurs during 
or after treatment, whether or not it is considered to be related to the protocol intervention. 
13.1.2 Serious Adverse Event (SAE) 
A serious adverse event is defined as any expected or unexpected adverse events that result in any of the 
following outcomes: 
 
Death 
 
Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Secondary malignancy* 
 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive treatment 
in the emergency room or at home, blood dyscrasias of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
*Modified from the definition of unexpected adverse drug experience in 21 CFR 312.32 
13.1.3 Unanticipated Problems Involving Risks to Subjects or Others 
An unanticipated problem is any incident, experience, or outcome that meets all three of the following 
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1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research protocol, 
informed consent document or Investigator Brochure (IB); and b) the characteristics of the subject 
population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the drugs, 
devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
13.1.4 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.   
13.1.4.1 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 v4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special interest 
according to Section 13.1.4 above. 
13.2 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, assessing the severity (i.e. 
grade), expectedness, and attribution of all adverse events.  
13.2.1 Assessment of Adverse Event Name and Grade 
Adverse events will be characterized using the descriptions and grading scales found in the most recent 
version of CTCAE v4.03.  A copy of the scale can be found at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html . The determination of severity for all other events not 
listed in the CTCAE v4.03 should be made by the investigator based on medical judgment and the 
severity categories of Grade 1 to 5 as defined below: 
• Grade 1 (mild) – An event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily living. 
• Grade 2 (moderate) – An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the subject. 
• Grade 3 (severe) – An event that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects the clinical status of the subject. 
• Grade 4 (life threatening) – An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that affect or limit the ability of the 
subject to perform activities of daily living (eating, ambulation, toileting, etc). 


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• Grade 5 (fatal) – Death (loss of life) as a result of an event. 
13.2.2 Assessment of Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study agent 
or study procedure. 
Unrelated -The event is clearly related to other factors such as the participant’s clinical state, other 
therapeutic interventions, or concomitant medications administered to the participant. 
Unlikely -The event is doubtfully related to the investigational agent. The event was most likely related 
to other factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
drugs. 
Possible –The event follows a reasonable temporal sequence from the time of drug administration, but 
could have been produced by other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
Probable - The event follows a reasonable temporal sequence from the time of drug administration, 
and follows a known response pattern to the study drug. The event cannot be reasonably explained by 
other factors such as the participant’s clinical state, therapeutic interventions, or concomitant drugs. 
Definite - The event follows a reasonable temporal sequence from the time of drug administration, 
follows a known response pattern to the study drug, cannot be reasonably explained by other factors 
such as the participant’s condition, therapeutic interventions, or concomitant drugs, AND occurs 
immediately following study drug administration, improves upon stopping the drug, or reappears on 
re-exposure. 
13.2.3 Assessment of Expectedness 
The following definitions will be used to determine the expectedness of the event: 
 
Unexpected - An adverse event is unexpected if it is not listed in the investigator’s brochure and/or 
package insert; is not listed at the specificity or severity that has been observed; is not consistent 
with the risk information described in the protocol and/or consent; is not an expected natural 
progression of any underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. *Modified from 21 CFR 312.32 (a). 
 
Expected – An adverse event is expected if it does not meet the criteria for an unexpected event, 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
13.3   Reporting of Adverse Events 
13.3.1 Routine reporting of Non-Serious Adverse Events by Site Investigators 
AEs will be collected from the signing of informed consent until ending study participation. Routine AE 
reporting will occur via data entry into the study eCRF. AEs will be monitored by the Protocol 
Management Team (PMT).  Adverse events that do not meet the criteria of serious OR are not 
unanticipated problems do not require expedited reporting. AEs reported through expedited processes (i.e. 
reported to the IRB, DSMC, FDA, etc.) must also be reported in routine study data submissions.   
AEs recorded in the eCRF include: 
o Highest Grade for all toxicities 
o All SAEs 


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13.3.2 Expediting Reporting Requirements of SAEs and UPs by Site Investigators 
13.3.2.1 Criteria for Reporting SAEs/Ups to the Coordinating Center 
Serious Adverse Events meeting the criteria specified below will be reported to the Coordinating Center 
within 24 hours of notification that the event occurred.  
Adverse events that require expedited reporting include: 
 
AEs or SAEs that meet the definition of an unanticipated problem 
 
All deaths that occur within 30 days of active treatment 
 
All deaths that occur after 30 days of active treatment that are unexpected and possibly, 
probably, or definitely related to the study agent or procedure 
 
All serious adverse events, regardless of relationship to study agent or study procedure, that 
occur within 30 days of the last day of treatment 
 
 All serious adverse events that occurred after 30 days of active treatment/therapy that are 
considered possibly, probably, or definitely related to the study agent or procedure  
Note: Follow-up reports must be submitted for all events that require expedited reporting when the status 
of the event changes and until the resolution or stabilization of the event. 
Reportable serious adverse events must be followed until the event is resolved, stabilized, or determined 
to be irreversible by the participating investigator; for ongoing reportable adverse events that are 
unrelated to study agent, the follow-up period may end at the 30-days post study-drug assessment. The 
Coordinating Center should be consulted prior to ending the follow-up of events that have stabilized. 
13.3.3 SAE Reporting to Local IRB 
13.3.3.1 Non COH Sites: Procedure for Reporting SAEs/UPs to the COH Data Coordinating Center 
1. Sites are to report to their local IRB per their sites’ specific institutional and IRB 
guidelines. As soon as possible, non-COH sites will provide to the COH Data 
Coordinating Center copies of the IRB submission and corresponding IRB 
response.  
2. Document/describe the SAE/UP on each of the following:  
a. 
MedWatch 3500A   
i. Downloadable form at http://www.fda.gov/medwatch/getforms.htm  
b. 
UP/SAE Coversheet 
i. SAE Coversheet is found in Appendix 6.  A modifiable Microsoft Word 
document is also available from the Data Coordinating Center.  An electronic 
signature on the document will be accepted. 
3. Scan and email above documents to DCC@coh.org with the subject title as 
“15334 SAE”.   
a. 
All SAE reports received at this account are forwarded immediately to 
study Principal Investigator, and to Coordinating Center personnel.  
b. 
While not required, if available and applicable, please also include the 
local IRB submission for this event in the submission.  


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4. If an email receipt from Coordinating Center personnel is not received within 
one working day, please call 626-218-7904 and/or email DCC@COH.org. 
13.3.3.2 COH Investigative Sites: Procedure for Reporting SAEs/Ups to the Coordinating Center 
1. Email the following information to DCC@coh.org and aherrera@coh.org.   
a. Participant ID, date the event met criteria for reporting, whether the event 
meets the definition of serious, whether the event is an unanticipated problem, 
grade of event, attribution of event, whether the event is a known expected 
toxicity to study agent. 
2. Complete the iRIS AE/UP reporting form per COH reporting timeline. 
13.3.4  Additional Reporting Requirements of the Study Principal Investigator 
13.3.4.1 Reporting to COH IRB and DSMC  
The study PI (or designee) will report to COH IRB and DSMC via iRIS all reportable serious adverse events 
that occur at COH and non-COH sites and meet COH IRB and DSMC expedited reporting criteria and 
occur at non-COH sites according to City of Hope’s Institutional policy. The study PI will also submit a 
Protocol Management Team (PMT) report to the COH DSMC at the frequency outlined in Section 15.6. 
this report will include a review of aggregate adverse event data.  
13.3.4.2 Reporting to the FDA 
The study PI (or designee) will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA 
will assist the PI with the preparation of the report and submit the report to the FDA in accordance with 
the approved City of Hope’s Institutional policy. 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using the 
MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the Medwatch 3500A are: 
 
Any unexpected fatal or life threatening adverse experience associated with use of the drug 
must be reported to the FDA no later than 7 calendar days after initial receipt of the information 
[21 CFR 312.32(c)(2)] 
 
Any adverse experience associated with use of the drug that is both serious and unexpected 
must be submitted no later than 15 calendar days after initial receipt of the information [21 
CFR 312.32(c)(1)] 
 
Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
In addition, the study PI will submit annually within 60 days (via COH OIDRA) of the anniversary date of 
when the IND went into effect, an annual report to the FDA which is to include a narrative summary and 
analysis of the information of all FDA reports within the reporting interval, a summary report of adverse 
drug experiences, and history of actions taken since the last report because of adverse drug experiences. 
13.3.4.3 Reporting to Participating Investigators 
The study PI (or designee) will report all reportable serious adverse events to participating investigators as 
an IND Safety Report occurring within 30 calendar days of receipt of sponsor (lead site) notification, and 
indicate whether or not a protocol and/or consent form change is required.  A cover letter will indicate the 


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protocol title, the IND#, whether the FDA was informed, and, for non-COH sites, a statement that the report 
should be submitted to their local IRB for review as an IND safety report if applicable per local IRB policy. 
The study PI will also forward to participating sites all IND safety reports received from Pharmacyclics, 
indicating whether a consent form or protocol change is required within 30 days of notification to study PI. 
 
13.3.4.4 Reporting to Pharmacyclics 
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 (AEintakePM@pcyc.com) or fax (408-215-3500) by the Study PI to Pharmacyclics Drug 
Safety, or designee, within 15 days of the event.  
The Study PI will report to Pharmacyclics summary safety information every three months. 
14.0 
Protocol Deviations and Single Subject Exceptions 
It is understood that deviations from the protocol should be avoided, except when necessary to eliminate an 
immediate hazard to a research participant. Brief interruptions and delays may occasionally be required 
because of travel delays, airport closures, inclement weather, family responsibilities, security alerts, 
government holidays, and so forth. Delays can also extend to complications of disease or unrelated medical 
illnesses not related to disease progression. The PI has the discretion to deviate from the protocol when 
necessary so long as such a deviation does not threaten patient safety or protocol scientific integrity. As a 
result of deviations, corrective actions are to be developed by the study staff and implemented promptly. 
14.1  Definitions 
14.1.1 Deviation 
A deviation is a divergence from a specific element of a protocol that occurred without prior IRB approval.  
Investigators may deviate from the protocol to eliminate immediate hazard(s) for the protection, safety, and 
well-being of the study subjects without prior IRB approval.  
Examples include, but are not limited to: a) dose adjustments based on excessive patient weight; b) 
alteration in treatment schedule due to non-availability of the research participant for treatment; and c) 
laboratory test results which are slightly outside the protocol requirements but at levels that do not affect 
participant safety. 
14.1.2 Single Subject Exceptions (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures 
called for in a protocol are not in the best interests of a specific patient.  It is a deviation that is anticipated 
and receives prior approval by the PI and the IRB.   
14.2  Reporting of Deviations and SSEs 
14.2.1 Reporting Deviations 
For any deviation, the Study PI will notify the COH DSMC and IRB within 5 calendar days of its occurrence 
via iRIS in accordance with the Clinical Research Protocol Deviation policy. 
A list of deviations from all participating sites will be submitted along with the Protocol Management 
Team (PMT) progress report to the COH DSMC. 
For non-COH sites:  
o The local IRB and/or DSMC must be notified according to local institutional policies.  


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o The study Principal Investigator must be notified as soon as practical (within 24 hours of 
notification of the event) via email to aherrera@coh.org and dcc@coh.org.  This email 
should provide input on the following: 
o Description of the event 
o Impact on participant safety or the safety to others 
o Impact on the study design 
o A corrective and preventative action plan 
14.2.2 Reporting Single Subject Exceptions 
The SSE must be submitted as a “Single Subject Exception Amendment Request” via iRIS in accordance 
with IRB guidelines and the Clinical Research Protocol Deviation policy.  An IRB approved SSE does not 
need to be submitted as a deviation to the DSMC. 
All non-emergency planned deviations from the protocol must have prior approval by the Study Principal 
Investigator, the Site Principal Investigator, COH IRB, and when applicable, the local IRB.  In addition, if 
contractually obligated, the sponsor must also approve the deviation. Any amendments to the Protocol or 
Informed Consent Form must be sent to Pharmacyclics for review and approval prior to submission to the 
IRB. 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring 
15.1 
All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, 
and welfare of subjects under the investigator's care; and for the control of drugs under investigation.  
All Investigators agree to: 
 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of subjects. 
 
Personally conduct or supervise the study (or investigation). 
 
Ensure that the requirements relating to obtaining informed consent and IRB review and approval 
meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
 
Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance with 
§21 CFR 312.64.  
 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for 
initial and continuing review and approval of the clinical study.  
 
Promptly report to the IRB and the Sponsor all changes in the research activity and all unanticipated 
problems involving risks to subjects or others (to include amendments and IND safety reports).  
 
Seek IRB and Sponsor (see Section 14) approval before any changes are made in the research study, 
except when necessary to eliminate hazards to the patients/subjects. 
 
Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in § 21 CFR part 312. 


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15.2 
Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities as defined in § 21 CFR 312. Subpart D are executed in accordance with federal 
regulations.  
 
15.3 
Protocol Management Team (PMT) 
The Protocol Management Team (PMT) minimally consisting of the study PI, site investigators, 
collaborating investigators, research nurse, clinical research associate/coordinator, and the study 
biostatistician, is responsible for ongoing monitoring of the data and safety of this study, including 
implementation of the stopping rules for safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) at least monthly to review study status. 
This review will include, but not be limited to, reportable AEs and UPs, and an update of the ongoing study 
summary that describes study progress in terms of the study schema. The meeting will be a forum to discuss 
study related issues including accrual, SAE/AEs experienced, study response, deviations/violations and 
study management issues. The appropriateness of further subject enrollment and the specific intervention 
for subsequent subject enrollment are addressed. It is recommended that minutes of these discussions will 
be taken to document the date of these meetings, attendees and the issues that were discussed (in a general 
format).   
15.4 
Monitoring  
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the study 
is implemented in accordance with the protocol and regulatory requirements, and that the quality and 
integrity of study data and data collection methods are maintained.  Monitoring for this study will be 
performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM), whose SOP 
is provided as a supplement to this document.   
The site Investigator/Institution will permit the study monitors and appropriate regulatory authorities direct 
access to the study data and to the corresponding source data and documents to verify the accuracy of this 
data. The Investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and 
has adequate space to conduct the monitoring visit. 
Details of clinical site monitoring are documented in the OCTAM SOP that is provided as a supplement to 
this document. This document specifies the frequency of monitoring, monitoring procedures, the level of 
clinical site monitoring activities (e.g., the percentage of subject data to be reviewed), and the distribution 
of monitoring reports. Staff from OCTAM will conduct monitoring activities and provide reports of the 
findings and associated action items in accordance with the City of Hope OCTAM SOP document.  
Documentation of monitoring activities and findings will be provided to the site study team, the site PI, 
study PI, and the COH DSMC. 
15.5 
Quality Assurance  
The City of Hope Clinical Research Information Support will provide support for this multi-center trial as 
detailed in the COH DCC Operations Plan provided as a supplement to this document.  
15.6 
City of Hope Data and Safety Monitoring Committee 
This is a Risk Level 4 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan 
(Appendix 8), as COH is the IND holder. 


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The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. The committee reviews the progress and 
safety of all active research protocols that are not monitored by another safety and data monitoring 
committee or board. 
The Study Principal Investigator is required to submit periodic status reports (i.e., the PMT Report) 
according to the frequency prescribed in the City of Hope Institutional Data and Safety Monitoring Plan 
(Appendix 7).  Data and safety will be reported to the COH DSMC using the PMT report and submitted 
quarterly from the date of activation. 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual 
data from this trial. The DSMC will review up-to-date participant accrual; summary of all adverse events 
captured via routine and expedited reporting; a summary of deviations; any response information; 
monitoring reports, and summary comments provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. A review of outcome results (response, toxicity and 
adverse events) and factors external to the study (such as scientific or therapeutic developments) is 
discussed, and the Committee votes on the status of each study. Information that raises any questions about 
participant safety will be addressed with the Principal Investigator, statistician and study team. The COH 
DSMC Charter is a supplement to this protocol. The PMT report and DSMC recommendations will be 
circulated to all participating sites for submission to their IRBs, in accordance with NIH guidance. 
16.0 
Ethical and Regulatory Considerations 
16.1 
Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
16.2 
Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the 
following considerations: 
 
US Code of Federal Regulations (CFR) governing clinical study conduct 
o Title 21 Part 11 – Electronic Records; Electronic Signatures  
o Title 21 Part 50 – Protection of Human Subjects  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
o Title 21 Part 56 – Institutional Review Boards  
o Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory 
Studies  
o Title 21 Part 312 – Investigational New Drug Application  
o Title 45 Part 46 – Protection of Human Subjects  
 
US Federal legislation, including but not limited to 
o Health Insurance Portability and Accountability Act of 1996  
o Section 801 of the Food and Drug Administration Amendments Act   
 
Applicable state and local laws. For research occurring in California, this includes but 
is not limited to State of California Health and Safety Code, Title 17 


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 
Applicable institutional research policies and procedures  
16.3 
Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate IRB holding a current US Federalwide Assurance issued by 
and registered with the Office for Human Research Protections (OHRP). Any documents that the IRB may 
need to fulfill its responsibilities (such as protocol, protocol amendments, Investigator’s Brochure, consent 
forms, information concerning patient recruitment, payment or compensation procedures, or other pertinent 
information) will be submitted to the IRB.  The IRB’s written unconditional approval of the study protocol 
and the informed consent document will be in the possession of the Investigator, and, for sites external to 
COH, the possession of the coordinating center, before the study is initiated. The Investigator will obtain 
assurance of IRB/IEC compliance with regulations. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional adverse 
experiences in accordance with the standard operating procedures and policies of the IRB; new information 
that may affect adversely the safety of the patients of the conduct of the study; an annual update and/or 
request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, as 
developed and provided by the Study PI, will require review and approval by the IRB before the changes 
are implemented in the study.  The protocol and consent will reviewed and approved by the COH IRB 
before submission to a participating site IRB. 
16.4 
Informed Consent 
For a multi-site study, each participating institution will be provided with a model informed consent form. 
Each institution may revise or add information to comply with local and/or institutional requirements, but 
may not remove procedural or risk content from the model consent form. Furthermore, prior to submission 
to the IRB (initial submission and amendments), the consent and accompanying HIPAA form, if separate 
to the consent, must be reviewed and approved by the Data Coordinating Center. 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his/her guardian or legal representative before study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent must comply with the ICH-GCP and all 
applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use of a written 
consent form approved by the IRB/IEC and signed and dated by the patient or the patient’s legally 
authorized representative at the time of consent.  A copy of the signed informed consent will be given to 
the patient or patient’s legally authorized representative.  The original signed consent must be maintained 
by the Site Investigator and available for inspection sponsor designated representatives, or regulatory 
authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study and 
continues throughout study participation.  
16.5 
Recruitment of Subjects 
Patients of both genders and all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria outlined in Section 3.0. To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another. Efforts will be made 


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to accrue a representative sample.  If differences in outcome appear to be associated with gender or ethnic 
identity, then a follow-up study will be designed to investigate those differences more fully. 
16.6 
Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to be 
posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and approved by 
the IRB prior to their use to recruit potential study subjects. 
16.7 
 Study Location and Performance Sites 
This study will be performed at COH, Cornell Medical College, UCSD and Ohio State Medical Center.   
16.8 
Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents.  This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and Accountability 
Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing the subject of 
the nature of the PHI to be collected, who will have access to that information and why, who will use or 
disclose that information, ant the rights of a research participant to revoke their authorization for use of 
their PHI. In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject authorization.  
For subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used. 
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements.   All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number. Source 
documents provided to the coordinating center for the purpose of auditing or monitoring will be de-
identified and labeled with the study number, subject ID, and patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. .  The patient’s confidentiality will be maintained and will not be made publicly available to 
the extent permitted by the applicable laws and regulations. 
 
16.9 
Financial Obligations and Compensation 
The investigational drug, Ibrutinib, will be provided free of charge by Pharmacyclics. The insurance carrier 
will be asked to pay for the cost of brentuximab vedotin since this drug is commercially available 


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The standard of care drugs and procedures provided will be the responsibility of the research participant and/or 
the insurance carrier. The research participant will be responsible for all copayments, deductibles, and other 
costs of treatment and diagnostic procedures as set forth by the insurance carrier. The research participant 
and/or the insurance carrier will be billed for the costs of treatment and diagnostic procedures in the same 
way as if the research participant were not in a research study. However, neither the research participant nor 
the insurance carrier will be responsible for the research procedures related to this study. 
In the event of physical injury to a research participant, resulting from research procedures, appropriate 
medical treatment will be available at the City of Hope to the injured research participant; however, financial 
compensation will not be available. 
The research participant will not be paid for taking part in this study. 
 
 


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17.0 
References 
1. 
Sutherland MS, Sanderson RJ, Gordon KA, et al: Lysosomal trafficking and cysteine protease 
metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol 
Chem 281:10540-7, 2006 
2. 
Younes A, Gopal AK, Smith SE, et al: Results of a Pivotal Phase II Study of Brentuximab Vedotin 
for Patients With Relapsed or Refractory Hodgkin's Lymphoma. J Clin Oncol 30:2183-2189, 2012 
3. 
Wilson WH, Gerecitano JF, Goy A, et al: The Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib 
(PCI-32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large 
B-Cell Lymphoma (DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study. ASH Annual 
Meeting Abstracts 120:686, 2012 
4. 
Wang ML, Rule S, Martin P, et al: Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-
Cell Lymphoma. New Engl J Med 369:507-516, 2013 
5. 
Byrd JC, Furman RR, Coutre SE, et al: Targeting BTK with Ibrutinib in Relapsed Chronic 
Lymphocytic Leukemia. New Engl J Med 369:32-42, 2013 
6. 
Connors JM: State-of-the-art therapeutics: Hodgkin's lymphoma. J Clin Oncol 23:6400-8, 2005 
7. 
Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. Ca-Cancer J Clin 58:71-96, 2008 
8. 
http://www.kantarhealth.com/services/epidemiology  
9. 
Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, 
https://www.cancer.ca  
10. 
Loge JH, Abrahamsen AF, Ekeberg O, et al: Reduced health-related quality of life among 
Hodgkin's disease survivors: A comparative study with general population norms. Ann Oncol 10:71-77, 
1999 
11. 
Swerdlow AJ, Barber JA, Hudson GV, et al: Risk of second malignancy after Hodgkin's disease in 
a collaborative British cohort: The relation to age at treatment. J Clin Oncol 18:498-509, 2000 
12. 
van Leeuwen FE, Klokman WJ, van't Veer MB, et al: Long-term risk of second malignancy in 
survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol 18:487-497, 
2000 
13. 
Horning SJ, Chao NJ, Negrin RS, et al: High-dose therapy and autologous hematopoietic progenitor 
cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results 
and prognostic indices. Blood 89:801-13, 1997 
14. 
Kleiner S, Kirsch A, Schwaner I, et al: High-dose chemotherapy with carboplatin, etoposide and 
ifosfamide followed by autologous stem cell rescue in patients with relapsed or refractory malignant 
lymphomas: a phase I/II study. Bone Marrow Transpl 20:953-9, 1997 
15. 
Francisco JA, Cerveny CG, Meyer DL, et al: cAC10-vcMMAE, an anti-CD30-monomethyl 
auristatin E conjugate with potent and selective antitumor activity. Blood 102:1458-65, 2003 
16. 
Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-
positive lymphomas. N Engl J Med 363:1812-21, 2010 
17. 
Nathwani N, Krishnan AY, Huang Q, et al: Persistence of CD30 expression in Hodgkin lymphoma 
following brentuximab vedotin (SGN-35) treatment failure. Leuk Lymphoma 53:2051-3, 2012 
18. 
Burger JA, O'Brien S, Fowler N, et al: The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is Well 
Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and 
Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies. ASH Annual Meeting 
Abstracts 116:57, 2010 


Page 57 of 67 
IRB Protocol No. 15334 
 
Version Date: 02/14/20 
Version: 16 
19. 
Bishop GA, Haxhinasto SA, Stunz LL, et al: Antigen-specific B-lymphocyte activation. Crit Rev 
Immunol 23:149-197, 2003 
20. 
Satterthwaite AB, Witte ON: The role of Bruton's tyrosine kinase in B-cell development and 
function: a genetic perspective. Immunol Rev 175:120-127, 2000 
21. 
Ibrutinib Investigator's Brochure Version 9: 30 June 2015  
22. 
Sagiv-Barfi I, Kohrt HEK, Czerwinski DK, et al: Therapeutic antitumor immunity by checkpoint 
blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. P Natl Acad Sci USA 112:E966-
E972, 2015 
23. 
Dubovsky JA, Beckwith KA, Natarajan G, et al: Ibrutinib is an irreversible molecular inhibitor of 
ITK driving a Th1-selective pressure in T lymphocytes. Blood 122:2539-2549, 2013 
24. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol 
32:3059-+, 2014 
25. 
Cheson BD, Pfistner B, Juweid ME, et al: Revised Response Criteria for Malignant Lymphoma. J 
Clin Oncol 25:579-586, 2007 
26. 
SGN-035 Investigator's Brochure  
27. 
Pan ZY, Scheerens H, Li SJ, et al: Discovery of selective irreversible inhibitors for Bruton's 
tyrosine kinase. Chemmedchem 2:58-61, 2007 
28. 
Herman SEM, Gordon AL, Hertlein E, et al: Bruton tyrosine kinase represents a promising 
therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. 
Blood 117:6287-6296, 2011 
29. 
Fanale M, Franklin A, Radhakrishnan R, et al: 9201 ORAL Complete Remissions Observed in a 
Subset of Pediatric Patients With CD30-expressing Malignant Lymphomas Treated in Clinical Studies of 
Brentuximab Vedotin (SGN-35). Eur J Cancer 47:S640 
30. Simon R (1989). Controlled Clinical Trials 10: 1-10.  
31. Jung SH, Lee TY, Kim KM, George S (2004). Admissible two-stage designs for phase II cancer clinical 
trials, Statistics in Medicine 23: 561-569. 
32. Chen R, Palmer J, Thomas S, Tsai N, Farol L, Nademanee A, Forman S, Gopal A. Brentuximab vedotin 
enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed 
or refractory Hodgkin lymphoma.  Blood 2012 Jun 28; 119(26):6379-81 
33. Chen R, Palmer JM, Martin P, Tsai N, Kim Y, Chen BT, Popplewell L, Siddiqi T, Thomas SH, Mott 
M, Sahebi F, Armenian S, Leonard J, Nademanee A, Forman SJ. Results of a Multicenter phase II trial of 
brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory 
Hodgkin lymphoma.  Biol Blood Marrow Transplant 2015 July 
34. Moskowitz A, Schöder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab 
vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and 
refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol 
2015 16:284-92.