A Phase 2 Study of Ibrutinib (PCI-32765) in Refractory Distant Metastatic Cutaneous Melanoma: Correlation of Biomarkers With Response and Resistance
Phase: PHASE2
Conditions: Metastatic Melanoma, Recurrent Cutaneous Melanoma, Stage IV Cutaneous Melanoma AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

i 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment #7  
 
NCI Protocol #: 9922 
Local Protocol #: NCI9922 
 
NCI Version Date: 05/08/2018 
Protocol Date: 05/08/2018  
 
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1.
Header 
Global 
Changed header date from August 27, 2017 to May 8, 2018 
2. Protocol 
cover 
page 
p. 2 
Version Date: May 8, 2018 
3. 2.2.1.4 
 
 
 
 
11 
Revised text to cite most recent version of Ibrutinib Investigator’s 
Brochure 
 
2.2.1.4 Summary of Clinical Data 
 
For more detailed and comprehensive information, please refer to the 
most recent Investigator’s Brochure for ibrutinib (version 11 10.2 
February November 2017). As of the April 6 2015 cutoff date, 26 
studies were ongoing and 19 studies had completed their primary 
analysis. 
 
4. 2.2.1.4.3 
 
14 
Revised text to cite most recent version of Ibrutinib Investigator’s 
Brochure 
2.2.1.4.3 
Summary of Safety 
Please refer to section 7.1.1.1 of this protocol and the most recent 
version of the Ibrutinib Investigator’s Brochure (November February 
2017) for the most up to date safety information on ibrutinib.  
 

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5.
3.1.21 
 
29 
Cite NCI CTCAE criteria v5.0 instead of 4.0. 
3.1.21 Subjects who are unable to tolerate BRAF inhibitor and/or MEK 
inhibitor therapy due to grade ≥2 toxicity (CTCAE v5.0 4.0) 
from these agents, irrespective of antitumor response, are eligible 
on condition that: (a) toxicities persisted despite change from 
doublet to singlet therapy (i.e. from concurrent BRAF inhibition 
plus MEK inhibition to BRAF inhibition alone), (b) toxicities are 
attributed to a class effect, and therefore switch from one drug to 
another is expected to induce the same type of toxicity (e.g. 
ocular toxicities or cardiac dysfunction from MEK inhibitor), (c) 
drug-specific toxicities that do not resolve with switch from one 
BRAF inhibitor to another (i.e. dabrafenib to vemurafenib, or 
vice versa), will be eligible for enrollment in 9922. In other 
words, patients will be allowed to enroll into the NCI9922 study 
despite lack of progression to MAPK inhibitor treatments, on 
condition that grade 2 or higher toxicities attributed to MAPK 
inhibitors resolve to grade 1, or less, at the time of study 
enrollment. 
 
6.
4.1 
32 
Please delete the language in these 2 subsections 4.1.1 and 4.1.2 and 
replace with the following, in accordance with the new Registration and 
Credentialing Repository language: 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to 
register and to renew their registration annually.  To register, all individuals 
must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician 
Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring 
write access to OPEN or RAVE or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPI
VR 
AP 
A 
FDA Form 1572 
 
 

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Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is 
required to access all CTEP and CTSU (Cancer Trials Support Unit) websites 
and applications.  In addition, IVRs and NPIVRs must list all clinical practice 
sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to 
allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR 
only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of 
Tasks Log (DTL).     
 
For questions, please contact the RCR Help Desk by email at < 
RCRHelpDesk@nih.gov >. 
 
 
7.
4.1 
32 
Please add the following sentence to the end of this section. 
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >. 
 
8.
4.2 
33 
Please revise this section as indicated: 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be approved to 

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enroll patients.  Assignment of site registration status in the CTSU Regulatory 
Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the 
following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a 
participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the 
following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form 
FDA 1572 
• An active status on a participating roster at the registering site 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be approved to 
enroll patients.  Assignment of site registration status in the CTSU Regulatory 
Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to: an active 
Federal Wide Assurance (FWA) number, an active roster affiliation with the 
Lead Network or a participating organization, a valid IRB approval, and 
compliance with all protocol specific requirements. 
 
 
9. 4.2.2 
34 
Please remove the first bullet as the CTSU Transmittal Sheet is no longer 
in use: 
 
• 
CTSU Transmittal Sheet (optional)  
 
10 4.2.3 
34 
Please update the CTSU Regulatory Office suite number to 3000. 
 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 1100 
Philadelphia, PA 19103 
11 4.2.3 
34 
Please remove the DTL requirement.  This is not designated as a 
protocol requiring DTL implementation. 
 
12 4.3.2 
36 
Please revise as indicated: 
 

v 
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OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and 
password). 
• To enroll patients or request slot reservations:  Be on an ETCTN 
Corresponding or Participating Organization roster with the role 
of Registrar. Registrars must hold a minimum of an AP 
registration type. If a DTL is required for this study, the 
registrar(s) must also be assigned the OPEN Registrar task on 
the DTL. 
• Have regulatory approval for the conduct of the study at their 
site. 
 
13 7.2 
49 
Cite NCI CTCAE criteria 5.0 instead of 4.0. 
 
• CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 5.0 will be utilized 
for AE reporting beginning April 1, 2018.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. 4.0  A 
copy of the CTCAE version 5.0 4.0 can be downloaded from the 
CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/
ctc.htm. 
 
14 12.3 
82 
Please revise the following paragraph as specified: 
Data collection for this study will be done exclusively through Medidata Rave.  
Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in the Regulatory Support System 
(RSS).  To access Rave via iMedidata, the site user must have an active CTEP 
IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site 
Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user 
must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. (https://eapps-ctep.nci.nih.gov/iam) and 
the appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on 
either the Corresponding Organization or Participating Organization roster at 
the enrolling site 

 
1 
NCI Protocol #: 
9922  
 
Local Protocol #: 
NCI9922 
 
ClinicalTrials.gov Identifier:  NCT02581930 
 
TITLE: A Phase 2 Study of Ibrutinib (PCI-32765) in Refractory Distant Metastatic Cutaneous 
Melanoma: Correlation of Biomarkers with Response and Resistance  
 
Corresponding Organization: LAO-NC010 / Duke University - Duke Cancer Institute LAO   
 
Principal Investigator: 
Stergios Moschos, MD 
University of North Carolina at Chapel Hill 
Physician’s Office Building, Suite 3116-CB#7305 
Chapel Hill, NC 27599 
Telephone: 919-843-7713 
Fax: 919-966-6735 
E-mail: stergios_moschos@med.unc.edu  
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO US sites only 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
2 
Statistician: 
Anastasia Ivanova, PhD  
  
University of North Carolina at Chapel Hill  
  
3103-C McGavran-Greenberg Hall  
  
135 Dauer Drive CB #7420 
  
Chapel Hill, NC 27599-7420 
  
Telephone: 919-843-8086 
  
E-mail: aivanova@bios.unc.edu 
 
 
Study Coordinator: 
 
Jen Reed 
 
 
 
UNC Cancer Network 
 
 
UNC Lineberger Cancer Center  
 
 
 
 
450 West Drive, Campus Box 7295  
 
 
 
 
Chapel Hill, NC 27599  
 
 
Telephone: 919-445-4211 
 
 
Fax:919-962-2621 
 
 
 
Jen_Reed@med.unc.edu 
 
 
Bob Broomer 
UNC Cancer Network 
UNC Lineberger Cancer Center                                                 
450 West Drive, Campus Box 7295                                           
Chapel Hill, NC 27599  
Telephone: 919-966-9257  
Fax: 919-962-9150                                                                        
 
 Bob_Broomer@med.unc.edu 
 
 
NCI-Supplied Agent:  
Ibrutinib (PCI-32765) (NSC 748645)  
 
Study Exempt from IND Requirements per 21 CFR 312.2(b) 
 
Study Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date:  Original / Version #1 / September 7, 2015 
Protocol Type / Version # / Version Date:  Version #2 / November 30, 2015 
Protocol Type / Version # / Version Date: Version #3 / January 6, 2016 
Protocol Type / Version # / Version Date: Version #4 / March 14, 2016 
Protocol Type / Version # / Version Date: Version #5 / April 15, 2016 
Protocol Type / Version # / Version Date: Version #6 / June 16, 2016 
Protocol Type / Version # / Version Date: Version #7 / July 07, 2016  
Protocol Type / Version # / Version Date: Version #8 / November 22, 2016 
Protocol Type / Version # / Version Date: Version #9 / December 12, 2016  
Protocol Type / Version # / Version Date: Version #10 / June 2, 2017 
Protocol Type / Version # / Version Date: Version #11 / July 25, 2017 
Protocol Type / Version # / Version Date: Version #12 / November 6, 2017 
Protocol Type / Version # / Version Date: Version #13 / May 8, 2018 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
3 
 
 
 
SCHEMA 
 
 
 
This is an open-label, single-arm, phase 2 trial designed to estimate the rate of objective response 
[OR: complete response (CR) + partial response (PR)] to ibrutinib administered as a single agent 
in up to 32 patients with immune checkpoint inhibitor-refractory (all patients) or immune 
checkpoint inhibitor ineligible and mitogen-activated protein kinase (MAPK) inhibitor-refractory 
(if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma. 
Patients will receive ibrutinib 840mg orally once daily, which is dose under investigation for 
refractory distant metastatic cutaneous melanoma, until intolerable toxicity, disease progression, 
or withdrawal from the trial.  Four weeks (28 days) will constitute a treatment cycle. Archived or 
freshly collected (immediately prior to enrollment to this study) tissue formalin-fixed paraffin 
embedded (FFPE) tumor blocks/slides will be requested at baseline to investigate tumor tissue-
based biomarkers of response. Peripheral blood will be collected at baseline, 4 weeks (day 29, 
i.e., day 1 of cycle 2), and at disease progression to explore ibrutinib-mediated effects on 
immune cell subsets associated with immunosuppression.  Additional correlative blood samples 
will be collected at specified time points for protein marker and pharmacogenomics exploratory 
analysis.

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
4 
TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objective ....................................................................................................6 
1.2 
Secondary Objective ................................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Metastatic Cutaneous Melanoma .............................................................................7 
2.2 
CTEP-supplied Agent ..............................................................................................8 
2.3 
Rationale ................................................................................................................18 
2.4 
Rationale for 840 mg dose of Ibrutinib ..................................................................25 
2.5 
Correlative Studies Background ..........................................................................266 
3. 
PATIENT SELECTION ....................................................................................................26 
3.1 
Inclusion Criteria ...................................................................................................26 
3.2 
Exclusion Criteria ..................................................................................................29 
3.3 
Inclusion of Women and Minorities ......................................................................31 
4. 
REGISTRATION PROCEDURES ...................................................................................32 
4.1 
Investigator and Research Associate Registration with 
CTEP .................................................................................................................324.2
 .................................................................................................................................................................... Site 
Registration ............................................................................................................33 
4.3 
Patient Registration ................................................................................................35 
4.4 
General Guidelines.................................................................................................36 
5. 
TREATMENT PLAN ........................................................................................................37 
5.1 
Agent Administration.............................................................................................37 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................38 
5.3 
Duration of Therapy ...............................................................................................39 
5.4 
Duration of Follow Up ...........................................................................................40 
5.5 
Criteria for Removal from Study ...........................................................................40 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................40 
6.1 
Ibrutinib..................................................................................................................40 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................44 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................44 
7.2 
Adverse Event Characteristics ...............................................................................49 
7.3 
Expedited Adverse Event Reporting ......................................................................49 
7.4 
Routine Adverse Event Reporting .........................................................................52 
7.5 
Secondary Malignancy...........................................................................................54 
7.6 
Second Malignancy ................................................................................................54 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
5 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................54 
8.1 
CTEP-supplied Agent ............................................................................................54 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................56 
9.1 
Integral Laboratory or Imaging Studies .................................................................56 
9.2 
Investigational Device Information .......................................................................56 
9.3 
Integrated/Exploratory Correlative Studies ...........................................................56 
9.4 
Exploratory/Ancillary Correlative Studies ............................................................62 
9.5 
Special Studies – Pharmacokinetic (PK) Study .....................................................67 
10. 
STUDY CALENDAR .......................................................................................................70 
11. 
MEASUREMENT OF EFFECT........................................................................................73 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................73 
11.2 
Other Response Parameters ...................................................................................79 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................80 
12.1 
Data and Safety Monitoring Plan ...........................................................................80 
12.2 
Data Reporting .......................................................................................................81 
12.3 
CTEP Multicenter Guidelines ................................................................................83 
12.4 
Collaborative Agreements Language .....................................................................83 
13. 
STATISTICAL CONSIDERATIONS...............................................................................85 
13.1 
Study Design/Endpoints.........................................................................................85 
13.2 
Sample Size/Accrual Rate ......................................................................................85 
13.3 
Toxicity Assessment ..............................................................................................86 
13.4 
Stratification Factors ..............................................................................................87 
13.5 
Analysis of Primary Endpoint ................................................................................87 
13.6 
Analysis of Secondary Endpoint ............................................................................87 
13.7 
Analysis of Exploratory Endpoints ........................................................................88 
13.8 
Reporting and Exclusions ......................................................................................88 
REFERENCES ..............................................................................................................................90 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................96 
APPENDIX B 
ADEQUACY OF ARCHIVED/FRESH TUMOR TISSUE ......................97 
APPENDIX C 
PATIENT DIARY FOR IBRUTINIB .......................................................99 
APPENDIX D 
INFORMATION ON POSSIBLE DRUG INTERACTIONS .................100 
APPENDIX E 
ARCHIVAL/FRESH TISSUE SUBMISSION FORM ...........................102 
APPENDIX F 
CHILD-PUGH SCORE ...........................................................................103 
APPENDIX G 
PBMC SHIPMENT LOG ........................................................................104 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
6 
APPENDIX H 
BIOMARKER SHIPMENT LOG ...........................................................105 
APPENDIX I                 PK SUBMISSION FORM .........................................................................14 
 
 
1. OBJECTIVES 
 
1.1 Primary Objective 
1.1.1 Estimate rate of objective response [OR: complete response (CR) + partial response (PR)]  
to ibrutinib administered as single agent in patients with immune checkpoint inhibitor-
refractory, or immune checkpoint inhibitor ineligible and MAPK inhibitor-refractory (if 
BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous 
melanoma. 
 
1.2 Secondary Objective 
1.2.1 Estimate progression-free survival (PFS) rate at 6 months after initiation of ibrutinib in  
patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible 
and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant 
distant metastatic cutaneous melanoma. 
 
1.2.2 Estimate overall survival (OS) after initiation of ibrutinib in patients with immune  
checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-
refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic 
cutaneous melanoma. 
 
1.2.3 Explore the association of ITK protein expression with OR and PFS. The ITK protein  
expression in melanoma cells (pretreatment) is assessed by 2-color immunofluorescence 
(IF)  in representative tissue sections obtained from archival FFPE tumor blocks or in 
representative tissue sections/slides obtained from freshly collected (immediately prior to 
enrollment to this study) biopsies from enrolled patients. 
 
1.3 Exploratory Objectives 
1.3.1 Explore association between other putative targets of ibrutinib (e.g. Tec, ErbB4, Hck,  
Yes, BTK) in melanoma cells, as assessed by 2-color IF in representative tissue sections 
obtained from pretreatment archived FFPE tumor blocks or FFPE blocks obtained from 
fresh tissue biopsy from enrolled patients, with OR and PFS. 
 
1.3.2 Explore ibrutinib-mediated effect(s) on immune cell subsets associated with  
immunomodulation by performing multiparameter flow cytometric analysis in PBMC 
obtained prior to treatment, on day 29 (i.e., predose day 1 of cycle 2) following initiation 
of treatment with ibrutinib, and at the time of disease progression (3 time points). 
 
1.3.3 Determine pharmacokinetics (PK) of ibrutinib following daily dosing at 840 mg on Day 8  
of cycle 1 (Css). 
 
 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
7 
 
2. BACKGROUND 
 
2.1 Metastatic Cutaneous Melanoma 
 
Metastatic cutaneous melanoma remains an active cancer type for further drug development 
despite the recent approval of 4 small molecule inhibitors targeting the MAPK pathway 
(Moschos et al., 2015) and 3 immunotherapies targeted against either the co-inhibitory molecules 
PD-1 (programmed cell death protein 1) or CTLA-4 (cytotoxic T-lymphocyte-associated antigen 
4)(Eggermont et al., 2015). Such treatments have prolonged OS either by stalling melanoma 
growth or by reversing inhibition of an occasionally present but usually dysfunctional (anergic) 
immune system. Durable responses lasting at least more than 3 years are possible following both 
treatment types (Sznol et al., 2015; Flaherty et al., 2016), and have possibly increased the 
incidence of cure in a small subgroup of patients, but in most cases disease ultimately becomes 
resistant (Atkins et al., 1999; Lebbe et al., 2014; Daud et al., 2015).  Several melanoma 
subgroups (cutaneous and non-cutaneous) have primary resistance despite these new effective 
treatments. 
 
The most recent evidence supporting the need for novel therapies comes from two randomized 
clinical trials in which inhibitory antibodies against PD-1 (nivolumab or pembrolizumab) were 
administered as a second- (i.e. following the anti CTLA-4 antibody ipilimumab) or third-line 
therapy (i.e. following ipilimumab and MAPK inhibitor-based therapy, if BRAFV600-mutant) 
versus investigator’s choice chemotherapy (ICC) in metastatic melanoma (Ribas et al., 2015; 
Weber et al., 2015). As shown in Table 1, OR by RECIST1.1 criteria ranged from ~20-30% for 
anti-PD1 therapy, as compared to 4% for ICC. The percent of patients alive and free of disease at 
6 months for pembrolizumab [data not available for nivolumab at the time of publication (Weber 
et al., 2015)] versus ICC was 34% and 16%, respectively, highlighting the need for additional 
approaches to treat metastatic cutaneous melanoma. 
 
Table 1.  PD-1 Antibody versus ICC as Second or Third-Line Treatment of Metastatic
Melanoma 
 
Nivolumab, 3mg/kg 
Q2wks 
ICC 
Pembrolizumab 2mg/kg 
Q3wks 
ICC 
N 
272 
133 
180 
179 
BRAFi (%) 
57 
31 
47 
43 
Rate of OR (%) 
32 
11 
21 
4 
PFS rate at 6 
months (%) 
Not reported (NR) 
NR 
34 
16 
 
We have recently shown that the non-receptor IL-2 inducible tyrosine kinase (ITK) is highly 
expressed in metastatic cutaneous melanoma and that its pharmacologic inhibition using the 
highly specific ITK inhibitor, BI10N, delays tumor growth in vitro as well as in various 
melanoma mouse models (Carson et al., 2015).  As shown below, ibrutinib, the recently FDA-
approved inhibitor of Bruton’s tyrosine kinase (BTK) that also inhibits other non-receptor 
tyrosine kinases including ITK, delayed cell proliferation in various melanoma cell lines. We 
would therefore like to conduct a phase II clinical trial of ibrutinib in distant metastatic 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
8 
cutaneous melanoma.  
 
2.2 CTEP-supplied Agent  
 
2.2.1 Ibrutinib (PCI-32765) 
 
Ibrutinib is a first-in-class, potent, orally administered, covalently binding inhibitor of Bruton’s 
tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen Research & 
Development LLC for the treatment of B-cell malignancies.   
 
Ibrutinib has been approved in many regions, including the US and EU, for indications covering 
the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia 
(CLL) who have received at least one prior therapy, first-line treatment of patients with CLL 
with a deletion of the short arm of chromosome 17 (del17p) or a TP53 mutation, and patients 
with Waldenström’s macroglobulinemia. Ibrutinib is currently under investigation in various 
indications as a single agent and in combinations. 
 
2.2.1.1 Mechanism of Action 
 
In vitro studies showed that ibrutinib binds covalently to a cysteine-481 residue (Cys-
481) near the BTK active site and inhibits the enzymatic activity with subnanomolar half-
maximal inhibitory concentration (IC50 0.5nM)(Pan et al., 2007; Honigberg et al., 2010).  
Covalent binding to Cys481 results in irreversible inhibition of BTK.  Other kinases that 
are inhibited by ibrutinib have been identified using an Ambit kinome screen, which is 
the basis for the current clinical proposal.  The inhibitory effect of ibrutinib against the 
activity of these kinases has been characterized in biochemical assays.  Only a small 
subset of kinases from the Tec and Src/abl family of kinase is predicted to contain a 
modifiable cysteine residue homologous to Cys481 in BTK, and therefore can be 
irreversibly modified by ibrutinib.  The other Cys-containing kinases include EGFR, 
HER2, HER4, Itk, Bmx, JAK3, Txk, Tec, and Blk. Ibrutinib also has reversible inhibitory 
activity against other kinases that do not contain Cys481(Honigberg et al., 2010).  
However, assuming a rapid off-rate, any reversible kinase inhibition in vivo is likely to be 
short-lived, since in humans the effective half-life of ibrutinib following oral dosing is 
only 1.5 to 3.3 hours (as measured from time of maximum drug concentration [Tmax] to 6 
hours after dose). 
 
A fluorescently-tagged derivative of ibrutinib was shown to bind to BTK in B-cell 
lysates, suggesting a high degree of specificity within B-cells (Honigberg et al., 2010).  
Thus, it was expected that ibrutinib would significantly occupy BTK within malignant 
cells of patients who had maximum plasma concentrations (Cmax) of ≥100nM.   
 
Therefore, by combining fast irreversible binding to BTK with rapid in vivo elimination, 
ibrutinib provides a unique approach to improve selectivity of BTK in vivo relative to 
reversibly inhibited off-target kinases.   
 
 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
9 
2.2.1.2 Cellular Selectivity of Ibrutinib 
 
BTK expression is limited to cells of hematopoietic origin.  The cellular selectivity of 
ibrutinib was demonstrated by the observation that ibrutinib inhibits antigen-receptor 
signaling in B-cells, but not in T-cells.  In ex-vivo stimulation assays, ibrutinib inhibits 
human BCR activation (IC50 <10nM) in B cells, but does not affect T-cell receptor 
activation (Honigberg et al., 2010).  It has also been determined that ibrutinib inhibits key 
phosphorylation events downstream of the BCR at similar concentrations.  Ibrutinib has 
been studied in other blood cell types where the function of BTK is understood, including 
mast cells, basophils, monocytes, macrophages, and platelets.  Consistent with the 
functional role of BTK in mast cells and basophils, it was determined that ibrutinib fully 
inhibits degranulation following stimulation at the high-affinity Immunoglobulin E (IgE) 
receptor (Chang et al., 2011; MacGlashan et al., 2011).  In monocytes and macrophages, 
ibrutinib inhibits the secretion of pro-inflammatory cytokines following stimulation at the 
Fc-gamma receptors (FcγR) by immune complex (Chang et al., 2011).  Consistent with 
the proposed function of BTK in platelets, ibrutinib inhibits shear-force and collagen-
induced platelet aggregation in vitro (IC50 10-100 nM) (Kamel et al., 2015). The latter 
may have implications in the treatment of patients who are prone to hemorrhage (i.e. 
post-surgery, on anticoagulation). 
 
2.2.1.3 Summary of Nonclinical Data 
 
For more detailed and comprehensive information, please refer to the most recent 
Investigator’s Brochure (IB) for ibrutinib. 
 
2.2.1.3.1   Nonclinical Pharmacology Studies 
 
As mentioned above, ibrutinib was designed as a selective and irreversible inhibitor 
of the BTK protein by inhibiting its autophosphorylation (Pan et al., 2007). The 
irreversible binding of ibrutinib to Cys481 in the active site of BTK enhanced 
selectivity over other kinases that do not contain a cysteine at this position. Ibrutinib 
potently and specifically blocked BCR-mediated lymphocyte activation in primary 
CD20+ human B cells (IC50 <10nM) whereas the T-cell receptor signaling remained 
intact at concentrations up to 1,000 nM. Furthermore, ibrutinib inhibited proliferation 
of cell lines derived from patients with diffuse large B-cell lymphoma (DLBCL), 
CLL at various concentrations ranging from low nM to sub µM in vitro (Zheng et al., 
2014) and inhibited tumor growth of OCI-Ly10 xenograft models with a once-daily 
oral gavage dose of 12mg/kg/day. 
 
Preclinical studies have also revealed a vital and multifaceted role for BTK and the 
BCR signaling pathway in B-cell leukemogenesis and lymphomagenesis. These data 
suggest that blockade of BCR signaling pathway by ibrutinib in CLL results in three 
major effects: 1) direct induction of apoptosis, 2) inhibition of cell homing and 
migration to chemokines and with subsequent adhesion to cellular substrates, and 3) 
inhibition of proliferation (Herman et al., 2011; Ponader et al., 2012).  Owing to the 
described mechanism of action of BTK inhibition, administration of ibrutinib to 

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patients with lymphoproliferative diseases has been associated with mobilization of 
tumor cells from lymph tissue to the peripheral blood compartment (Advani et al., 
2013). 
 
As mentioned above, it is important to emphasize that ibrutinib potently and 
irreversibly inhibits various other kinases that contain the conserved Cys481 site, in 
particular those of the Tec and Src/abl family. In particular, the median IC50 values 
are subnanomolar for ErbB4/HER4 and Blk, in addition to Btk; between 1-5nM for 
Bmx/Etk, Fgr, Txk, Lck, and Yes/YES1; between 5-10nM for Tec, Csk, and EGFR; 
between 10-15nM for Brk and Itk; between 15-22 nM for Hck, ErbB2/HER2 and 
JAK3 (Investigator’s Brochure 2015 and(Honigberg et al., 2010)). These “off-target” 
effects of ibrutinib may account for several immunomodulatory(Stiff et al., 2016) and 
direct antitumor effects that have been observed with ibrutinib in CLL (Dubovsky et 
al., 2013), T-cell driven, and alloantibody-driven graft-versus-host-disease (cGVHD) 
models (Dubovsky et al., 2014), non-small cell lung cancer cell lines (Gao et al., 
2014), pancreatic cancer models (Masso-Valles et al., 2015; Gunderson et al., 2016), 
lymphoma (Sagiv-Barfi et al., 2015) and breast cancer (Wang et al., 2016). The 
results from these studies suggest that ibrutinib, by being a highly potent and 
irreversible inhibitor of various kinases, can have antitumor effects beyond the 
originally observed clinical benefit in BTK-driven malignancies. 
  
2.2.1.3.2  Toxicology Studies 
 
Ibrutinib toxicity following a single po dose as well as repeated po dose of up to 6 
months were conducted in rats, and up to 9 months in beagle dogs. The maximum 
nonlethal total dose of ibrutinib following administration by oral gavage was 
2,000mg/kg for mice (human equivalent dose [HED] =160mg/kg), 400 mg/kg for 
female rate (HED =63mg/kg), and 1,000mg/kg for male rates (HED =160mg/kg), 
whereas the no-observed-adverse-effect level (NOAEL) was 30mg/kg/day (HED 
=16.2mg/kg/day). Lymphoid depletion in central and peripheral organs, inflammation 
of intestines, body weight gain and food intake, as well as squamous epithelial 
atrophy in some tissues (stomach, pancreas) was observed at high dose levels in the 
13-week study. These histopathologic changes were fully reversible within 6 weeks 
after treatment cessation. 
 
In dogs the no-observed-adverse-effect level was 30mg/kg/day (HED 
=16.2mg/kg/day) whereas the NOAEL for ibrutinib once daily by oral gavage for up 
to 9 months was 80mg/kg/day (HED=44.4mg/kg/day). Similar reversible 
histopathologic changes to rats and mice were also seen in dogs (intestinal 
inflammation, lymphoid depletion) at the top dose (80mg/kg/day) administered over 9 
months or at an even higher dose (220mg/kg/day) administered over up to 13 weeks 
(Investigator’s Brochure, 2015).  A cardiac study in telemetry-monitored dogs (single 
doses of 24 and 150mg/kg) has also been performed (Investigator’s Brochure, 2015).  
This study identified increased PR interval, lower heart rate and QTc with the 
NOAEL identified as 24mg/kg/day. 
 

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2.2.1.3.3   Pharmacokinetics and Metabolism 
 
Orally administered ibrutinib was rapidly absorbed with ≤ 25% oral bioavailability in 
rats and dogs. Pharmacokinetic studies using orally administered 14C-labeled ibrutinib 
showed wide distribution in most tissues at 1 hour after dosing, with plasma 
exhibiting the highest levels followed by the liver whereas central nervous system 
organs (brain, spinal cord and eye) exhibited the lowest concentrations. Ibrutinib is 
metabolized in various laboratory animals and humans by CYP3A and primarily via 3 
metabolic pathways. (1) hydroxylation of the phenyl moiety, (2) opening of the 
piperidine with further reduction to a primary alcohol or oxidation to a carboxylic 
acid, and (3) epoxidation of the acrolein moiety followed by hydrolysis to form 
dihydrodiol ibrutinib of PCI-45227.  This metabolite is a reversible inhibitor of BTK 
with an IC50 of 6.2nM (2.95ng/mL).  Because of lower intrinsic potency relative to 
the parent ibrutinib and a reversible mechanism of action, PCI-45227 most likely 
does not contribute significantly to the overall pharmacologic activity of orally 
administered ibrutinib. Ibrutinib is not a substrate for P-glycoprotein (P-gp) or other 
major transporters substrate, but is a mild inhibitor of P-gp and the breast cancer 
resistance protein, BCRP. 
 
Ibrutinib is an inhibitor of several CYP450 isoenzymes, with IC50 values ranging 
from 4.23 to 11.0µg/mL (Investigator’s Brochure, 2015).  Because of the wide 
separation between these inhibitory concentrations and the expected maximum 
plasma levels in patients, inhibition of CYP450 metabolism in humans is not 
expected.  The metabolite PCI-45227 is a weak inhibitor towards CYP450 
isoenzymes, with IC50 values ranging from 8.1 to 36.1µg/mL.  Inhibition of CYP450 
metabolism by PCI-45227 is not expected to occur in humans.  The metabolite PCI-
45227 is a P-gp substrate, but is not an inhibitor of P-gp.  
 
In rats, dogs, and humans, excretion of the ibrutinib-related radioactivity occurred 
principally via feces. Biliary excretion was confirmed as a major route of 14C-
ibrutinib-derived radioactivity in rats. Less than 2-3.3% and between 5.5-9.3% of the 
administered radioactivity was recovered in urine from rats/dogs and humans, 
respectively.  
 
2.2.1.4 Summary of Clinical Data 
 
For more detailed and comprehensive information, please refer to the most recent 
Investigator’s Brochure for ibrutinib (version 11 November 2017). As of the April 6 2015 
cutoff date, 26 studies were ongoing and 19 studies had completed their primary analysis. 
More specifically, 143 subjects have been treated in 7 studies (all complete) involving 
healthy subjects. A total of 1,071 patients have been treated with ibrutinib monotherapy 
and 423 patients were treated with ibrutinib in combination with chemotherapy or 
immunotherapy. Of these, 345 patients with B-cell lymphoma in a total of 6 studies (3 
ongoing) (Advani et al., 2013). There are 11 ongoing/completed studies in patients with 
CLL/SLL (6 ongoing, 5 complete)(Byrd et al., 2013; Burger et al., 2014; Byrd et al., 
2014; O'Brien et al., 2014; Brown et al., 2015; Byrd et al., 2015; Farooqui et al., 2015; 

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Jaglowski et al., 2015), 5 studies in patients with MCL (2 complete, 3 ongoing)(Wang et 
al., 2013; Wang et al., 2015), 4 ongoing/completed studies in patients with DLBCL (one 
complete, 3 ongoing)(Maddocks et al., 2015; Wilson et al., 2015), 3 ongoing studies in 
follicular/marginal zone lymphoma (FL/MZL)(Younes et al., 2014), 2 studies in 
Waldenström’s macroglobulinemia (one complete, one ongoing)(Treon et al., 2015),  2 
ongoing studies in multiple myeloma (MM), and a single ongoing study in each of the 
following diseases: MZL, chronic graft-versus-host disease and acute myelogenous 
leukemia (Appendix A, Investigator’s Brochure, 2015).  
 
Of the studies described above, 36 normal subjects (2 studies; CLL1007, CLL1008), 
approximately 60 patients with CLL/SLL (1102), approximately 35 patients with MM 
(1111, 1119), have received ibrutinib at a daily dose of 840mg, either alone or in 
combination with chemotherapy and or immunotherapy. Finally, the following 
randomized phase III studies are being conducted in: (a) CLL/SLL (total of six studies; 
for example, ibrutinib alone versus single-agent chlorambucil, single-agent ofatumumab, 
or single-agent rituximab OR ibrutinib in combination with bendamustine versus 
bendamustine alone OR ibrutinib in combination with obinutuzumab versus chlorambucil 
plus obinutuzumab OR ibrutinib based induction therapy versus FCR), (b) MCL [total of 
two studies; ibrutinib alone versus temsirolimus AND ibrutinib plus bendamustine plus 
rituximab (BR) versus BR alone], (c) DLBCL (a single study of ibrutinib plus R-CHOP 
versus R-CHOP alone), (d) FL/MZL (a single study of ibrutinib in combination with BR 
or R-CHOP versus BR alone or R-CHOP alone), (d) Waldenström’s macroglobulinemia 
(a single study of ibrutinib in combination with rituximab versus ibrutinib alone).  
 
2.2.1.4.1   Summary of Pharmacokinetics 
 
Extensive pharmacokinetic (PK) analysis has been performed in approximately 250 
healthy individuals as well as patients with various B-cell malignancies across five 
studies. Following oral administration of doses ranging from 1.25mg/kg to 12.5mg/kg 
as well as a fixed-dose level of 560mg daily, area-under-the-curve (AUC) values for 
ibrutinib increased in an approximate dose-proportional manner with substantial 
inter-subject variability (Investigator’s Brochure, 2012).  The coefficient of variation 
for the AUC ranged from 60% to 107% across all studies.  Administration of ibrutinib 
in a fasted condition resulted in approximately 60% of exposure as compared to 
administration either in fed condition (30 minutes after a high-fat breakfast) or when 
drug was taken 30 minutes before or 2 hours after a meal. The plasma protein binding 
of ibrutinib and PCI-45227 in human plasma is 97.3% and 91%, respectively and the 
apparent steady-state volume of distribution was approximately 10,000L, suggesting 
extensive distribution to peripheral tissues and/or binding to macromolecules in the 
circulation. The mean terminal half-life (t1/2) of ibrutinib ranged from 4.3 to 8.9 
hours, with median Tmax of 2 hours.  There was no apparent accumulation of ibrutinib 
exposure after repeated daily oral dosing. Ibrutinib was extensively metabolized and 
predominantly cleared by 3 primary cytochrome P450 (CYP)3A-mediated metabolic 
pathways, one of them being epoxidation of the acryloyl moiety, followed by 
hydrolysis to form dihydrodiol metabolite PCI-45227.  The metabolite-to-parent 
AUC ratio ranged from 1.4 to 3.2.  Consistent with the profile observed for ibrutinib, 

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there was no apparent accumulation of PCI-45227 in the plasma after repeated daily 
oral dosing of ibrutinib.  Metabolite PCI-45227 is a reversible inhibitor of BTK with 
approximately 1/10th the inhibitory potency of ibrutinib.  Excretion is predominantly 
via the feces with 80% recovered mostly within 2 days, whereas 8% was excreted in 
urine.  
 
Effects of ibrutinib on the PR and QT interval were studied in 125 subjects with 
CLL/SLL who underwent central electrocardiogram monitoring. There as a clinically 
insignificant, dose-independent QTcF interval shortening by an average of 7.5ms and 
PR interval increase by an average of 9.7ms relative to baseline in CLL/SLL subjects 
who were dosed with 420mg/d or 840mg/day. 
 
With the exception of the hepatic impairment study, no special population was 
formally studied. The recommended doses for patients with mild, moderate and 
severe impairment are 280mg/day and 140mg/day (Child-Pugh Class A and B, 
respectively). Nevertheless, clinical development of ibrutinib included a large number 
of patients >65 years old. In the pharmacokinetic studies performed variables, such as 
sex, race, and renal impairment were not significant.  
 
In accordance with the role of CYP3A pathways in ibrutinib metabolism, co-
administration of ketoconazole, a strong CYP3A inhibitor in 18 healthy subjects 
increased exposure (Cmax and AUClast) of ibrutinib by 29- and 24-fold, respectively. 
Grapefruit juice, which inhibits intenstinal CYP3A and therefore influences the first-
pass effect, induced a 2- and 4-fold increase in ibrutinib’s AUClast and Cmax, 
respectively. In contrast, 600mg daily of oral rifampin, a strong CYP3A inducer, in 
combination with 560mg of ibrutinib 18 healthy fasted males and females led to 
reduction of AUClast and Cmax of ibrutinib by 90% and 92%, respectively. 
 
2.2.1.4.2  Summary of Pharmacodynamics 
 
Pharmacodynamics of ibrutinib were determined in 2 studies in subjects with B-cell 
malignancies by monitoring the BTK active-site occupancy in subjects’ peripheral 
blood mononuclear cells (PBMC) before and after ibrutinib treatment. These studies 
showed that subjects administered ibrutinib at doses greater or equal to 2.5mg/kg/day 
achieved more than 90% occupancy at 4 and 24 hours after drug administration. 
Therefore, to ensure achievement of the full pharmacodynamics effect in the vast 
majority of patients, fixed dose levels >280mg were likely necessary. In support of 
the latter, results from a phase 2 study in patients with CLL who received ibrutinib 
administered at 420mg/day and 840mg/day confirmed that the median BTK 
occupancy was >90% on all treatment days examined, including the 24-hour post-
dose on day 1 and pre-dose on day 8 of the first week of treatment.  
 
 
 
 
 

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2.2.1.4.3 Summary of Safety 
 
 
Please refer to section 7.1.1.1 of this protocol and the most recent version of the 
Ibrutinib Investigator’s Brochure (November 2017) for the most up to date safety 
information on ibrutinib.  
 
Overall Adverse Events in Patients Taking Ibrutinib Monotherapy  
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 
9 studies in B-cell malignancies, which includes subjects from two randomized-control 
studies who crossed over from comparator treatment or placebo to receive ibrutinib 
monotherapy, are summarized below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects 
receiving ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs >10%   
Most frequently reported 
Grade 3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 
 
Overall Adverse Events in Patients Taking Ibrutinib Combination Therapy  
Pooled safety data for a total of 423 subjects treated with various therapies in 
combination with ibrutinib from 4 studies conducted in B-cell malignancies, which 
included one randomized-control study, are summarized below. Therapies used in 
combination with ibrutinib in these studies, included BR (bendamustine and 
rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), ofatumumab, and 
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).  
Most frequently reported 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  
 
 
Bleeding-related Events   
There have been reports of hemorrhagic events in subjects treated with ibrutinib, 
both with and without thrombocytopenia. These include minor hemorrhagic 
events, such as contusion, epistaxis, and petechiae; and major hemorrhagic events, 
some fatal, including gastrointestinal bleeding, intracranial hemorrhage, and 

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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.  
 
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). 
The most commonly reported infections include pneumonia, cellulitis, urinary 
tract infection and sepsis. Although causality has not been established, cases of 
progressive multifocal leukoencephalopathy (PML) have occurred in patients 
treated with ibrutinib. 
 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and 
anemia) were reported in subjects treated with ibrutinib.  
 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with 
ibrutinib, particularly in subjects with cardiac risk factors, acute infections, and a 
previous history of atrial fibrillation. For atrial fibrillation that persists, consider 
the risks and benefits of ibrutinib treatment. 
 
Second Primary Malignancies 
Second primary malignancies, most frequently skin cancers, have occurred in 
subjects treated with ibrutinib. Second primary malignancies including non-skin 
carcinomas have occurred in patients treated with ibrutinib. The most frequent 
second primary malignancy was non-melanoma skin cancer.  
 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated 
with single-agent ibrutinib or in combination with chemotherapy. Subjects at risk 
of TLS are those with comorbidities and/or risk factors, such as high tumor 
burden prior to treatment, increased uric acid, elevated lactate dehydrogenase 
(LDH), bulky disease at baseline, and pre‐existing kidney abnormalities. 
 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib 
monotherapy and combination therapy. Other frequently reported gastrointestinal 
events include nausea, vomiting, and constipation. These events are rarely severe.  
 
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.  

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Treatment-Related Lymphocytosis 
Similar to other agents targeting B-cell receptor signaling, transient 
lymphocytosis is a pharmacodynamic effect of ibrutinib, in which the inhibition 
of BTK-mediated cellular homing and adhesion results in a mobilization of tumor 
cells to the peripheral blood (Chang et al., 2013). 
 
Upon initiation of treatment, a transient phase of increase in lymphocyte counts 
(i.e., ≥50% increase from baseline and above absolute count 5000/mcL), often 
associated with reduction of lymphadenopathy, has been observed in most 
patients (75%) with relapsed/refractory CLL/SLL treated with ibrutinib. This 
effect has also been observed in some patients (33%) with relapsed/refractory 
MCL treated with ibrutinib.  This observed transient lymphocytosis is usually not 
associated with an AE 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 resolves within a median of 7.1 weeks in the MCL and 18.7 weeks in the CLL 
patients. 
 
A substantial increase in the number of circulating lymphocytes (>400,000/mcL) 
has been observed in a subset of patients. There have been isolated cases of 
leukostasis reported in patients treated with ibrutinib.  
 
A high number of circulating malignant cells (>400,000/mcL) may confer 
increased risk; these patients should be closely monitored. Administer supportive 
care, such as hydration and/or leukophoresis, is indicated. Ibrutinib may be 
temporarily held, and medical monitor should be contacted. 
 
Hemorrhagic Adverse Events 
There are reports of hemorrhagic events in patients treated with ibrutinib in both 
monotherapy and combination clinical studies.  The majority of these 
hemorrhagic adverse events were of grade 1 or 2 in severity, including minor 
hemorrhagic events, such as contusion, epistaxis and petechiae; and major 
hemorrhagic events including gastrointestinal bleeding, intracranial hemorrhage 
and hematuria.  Hemorrhagic events of grade 3 or higher, including central 
nervous system hemorrhage of any grade severity, occurred in 3.4% (17/506) of 
patients treated in monotherapy studies and in 3.1% (4/130) of patients treated in 
combination therapy studies. It is not clear whether or not these events are 
attributable to ibrutinib. However, it is possible that treatment with the study drug 
could increase the risk of bruising or bleeding. 
Patients were excluded from participation in ibrutinib phase 2 and 3 studies if 
they required warfarin or other vitamin K antagonists.  Do not administer 
ibrutinib concomitantly with warfarin or other vitamin K antagonists.  Ibrutinib 
should be used with caution in patients requiring other anticoagulants or 
medications that inhibit platelet function.  Patients receiving antiplatelet agents in 

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conjunction with ibrutinib should be observed closely for any signs of bleeding or 
bruising and ibrutinib should be withheld in the event of any bleeding events.  
Supplements, such as fish oil and vitamin E preparations, should be avoided. 
Patients with congenital bleeding diathesis have not been studied. 
Patients in the current study will be monitored closely for hemorrhagic AEs. 
Ibrutinib should be held at least 3 to 7 days pre and post-surgery depending upon 
the type of surgery and the risk of bleeding. [NOTE: Please refer to prohibitions 
and restrictions for further details.] 
 
2.2.1.4.4   Summary of Efficacy  
 
Efficacy data are available in 1,494 subjects who received ibrutinib either as 
monotherapy or combination therapy across 13 studies (10 studies in patients with 
pure B-cell malignancies; 3 studies in patients with mixed B-cell malignancies; see 
Table 24 Investigator’s Brochure 2015).  In summary, in the first-in-human phase 1, 
dose-escalating study (PCYC-04753), overall response rate in the efficacy evaluable 
population (n=54) was 57% (18% complete response; 39% partial response). 
Responses were observed across all B-cell histologies enrolled, with the highest 
response rates in CLL/SLL and MCL (85% each) and lower response rates in DLBCL 
and non-Hodgkin’s lymphoma (33% each). PCI-32765DBL1102 was a phase 1b, 
open-label, non-randomized, multicenter, dose-escalation and expansion study to 
establish the recommended phase 2 dose of ibrutinib (280mg, 420mg, 560mg) in 
combination with standard R-CHOP in patients with CD20-positive treatment-naïve 
B-cell NHL. The ibrutinib plus R-CHOP combination demonstrated clinical activity 
across all dose cohorts in the all-treated population with ORR 85.7%, 100%, and 
95%, respectively. 
 
Study 1112, was a randomized phase 3 of ibrutinib versus ofatumumab in patients 
with CLL/SLL. Ibrutinib was superior to ofatumumab in both ORR (42.6% versus 
4.1%) and risk of death (HR=0.215, p<0.0001). Long-term follow up in subjects with 
CLL/SLL who received ibrutinib as front-line versus following previous treatment, as 
part of the 1102 and 1103 trials, showed that higher clinical benefit of upfront 
ibrutinib therapy in both OR (90.3% versus 79.2%) and 30-month PFS rate (96.3% 
and 68.4%).  
 
A number of studies have combined ibrutinib with standard treatments in patients 
with CLL/SLL. In the study CLL3001, the addition of ibrutinib to BR, as compared 
with placebo plus BR, significantly improved OR (82.7% vs. 67.8%, p<0.0001) and 
prolonged PFS (HR=0.203, 95% CI: 0.150, 0.276). In study 1109 the addition of 
ibrutinib in combination with ofatumumab across three dosing sequences resulted in 
high OR (81.7%, per investigator assessment) and PFS (12-month PFS rate 83.1%).  
 
A number of phase II studies of ibrutinib administered as single agent have shown 
promising clinical benefit across non-CLL/SLL B-cell malignancies (1104, 
MCL2001, 1106, 1118E).  

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2.3 Rationale 
 
Our interest to investigate the antitumor effect of ibrutinib in distant metastatic cutaneous 
melanoma was developed following studies to characterize the role of ITK, one of ibrutinib’s 
high affinity targets (Honigberg et al., 2010; Dubovsky et al., 2013), in cutaneous melanoma. 
This section describes our preclinical investigations, which suggest that ITK is a potential 
therapeutic target in melanoma (Carson et al., 2015).  Since ITK is a high affinity target for 
ibrutinib, we proceeded to characterize the direct antitumor role of ibrutinib in various melanoma 
cell lines with variable degree of expression of ITK by fluorescent immunocytochemistry (IHC). 
Our results show that ibrutinib has a direct antitumor effect by at least delaying melanoma cell 
growth and that this effect is primarily mediated via ITK. Nevertheless, given that ibrutinib has 
several high affinity targets with a potential role in melanoma (see Table 2), we do not exclude 
the possibility that ibrutinib’s antitumor effect may, in addition, be dependent on the expression 
and functions of other kinases by melanoma cells. 
 
2.3.1 Role of ITK in Melanoma; In-vitro  
 
The promoter for the ITK gene, a member of the TEC family of non-receptor tyrosine kinases 
that also includes BTK, among others, was found to be significantly hypomethylated in primary 
cutaneous melanomas compared with nevi (Conway et al., 2011). To investigate this 
paradoxically aberrant expression of ITK in cutaneous melanomas, a tyrosine kinase that was 
previously thought to be exclusively expressed in immune cell subset, we evaluated the 
expression pattern of ITK in cutaneous melanomas, its in vitro role in various melanoma cell 
lines, and the effects of a highly selective small molecule ITK inhibitor, BI 10N, in various 
mouse models (Riether et al., 2009). In summary, analysis of the proteomic effects of BI 10N in 
melanoma cells suggest moderate-to-minimal effects on the most frequently involved signaling 
pathways in melanoma development and tumor progression, namely Ras-Raf-MEK-ERK and 
PI3K-Akt-mTOR. In contrast, significant suppression of EGFR- and FAK-mediated signaling 
and increases in AMPKa and p53/MDM2 protein levels were seen. In addition, Ingenuity 
pathway analysis, a web-based software application for the analysis, integration, and 
interpretation of data derived from ‘omics experiments (Ganter et al., 2008), has shown effects 
on TP53 signaling and moderate effects on cytoskeleton and extracellular matrix components 
that cannot fully account for the effect of ITK inhibition on cell motility. 
 
Details on UNC In Vitro Experiments 
In our hands, BI 10N exhibited kinase selectivity against ITK (IC50 at 1mM [ATP] 1.43nM), 
neurotrophic tyrosine kinase receptors type 1, 2 and 3 (NRTK1, 2, and 3; IC50 0.82nM, 1.28nM, 
and 1.58nM, respectively), and the non-receptor tyrosine kinase YES (IC50 5.9nM). The results 
are summarized as follows (Carson et al., 2015):  
 
• Expression of ITK protein, as determined by 2-color immunofluorescence (IF) is 
significantly increased along the nevus-to-melanoma progression pathway with the highest 
expression in metastatic cutaneous melanoma (both regional lymph node positive as well as 
distant metastatic melanoma). ITK expression is significantly correlated with melanoma 

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19 
protein expression of PD-1 ligand 1 (PD-L1), but is unrelated to melanoma protein 
expression of activated AKT (pAKTSer473), PTEN, activated ERK (pErk1/2Thr202/Tyr204), and 
BRAFV600E status. 
 
• Suppression of ITK mRNA expression using short hairpin (sh) RNA technology, or 
pharmacologic inhibition of ITK using BI 10N, inhibits melanoma cell growth and impairs 
melanoma cell motility without appreciable effects on cell death. 
 
• Reverse phase protein array analysis of approximately 180 proteins in their total or 
phosphorylated form was performed on whole cell protein extracts obtained from melanoma 
cell lines that were treated with up to 50nM of BI 10N: 
 
o With respect to effects on signaling pathways RAF-MEK-ERK and PI3K-Akt-mTOR we 
saw minimal or no effect on components of the PI3K/AKT/mTOR signaling  
[PI3Kp110/p85, PTEN, pMTOR(S2448)/MTOR, pAkt(S473,T308)/Akt, RSK, TSC1, 
pP70S6K(T389)/P70S6K, pPRAS40(T246)/PRAS40, pRICTOR(T1135)/RICTOR, S6 
[pS6(S235,S236), pS6(S240,S244)], pTuberin(T1462)/Tuberin, Rheb]. Similarly, 
minimal or no effects on the RAS/RAF/MEK1/ERK signaling [NRAS, 
pBRAF(S445)/BRAF, pCRAF(S338)/CRAF, pMAPK(T202,Y204), 
pMEK1(S217,S221)/MEK1] were seen.  
 
o With respect to effects on other signaling pathways, we saw marked reduction in 
pEGFR(Y1068)/EGFR, marked increase in pAMPKaT172/AMPKa, smaller increase 
in pHER3(Y1289)/HER3 (but not pEGFRY1173/EGFR, or heregulin signaling), 
reduction in pP38(T180,Y182)/P38,  marked increase in pHSP27(S82)/HSP27, reduction 
in pPEA15(S116)/PEA15, reduction in PLK1, and reduction in Tyro3. No effect was 
seen on cMET [pcMet(Y1234,Y1235)/cMET], PKCα [pPKCα(S660)/PKCα], Src 
[pSrc(Y416,Y527)/Src)], FoxO3α [pFoxO3α(S318,S321)/FoxO3α], GSK3α [pGSK3α 
(S21)/GSK3α], IGF1R [pIGF1R(Y1135,Y1136)/IGF1R], NFκBp65 (S536), PKCβ 
(S660), PKCδ (S664), PLCγ2 (Y759), STAT3 [pSTAT3(Y705)/STAT3], STAT5α, YAP 
[pYAP(S127)/YAP], YB1 [pYB1(S102)/YB1], Aurora B, PDGFRβ, c-Kit, IRF1, Lck, 
IRS1, or β-catenin [pβ-catenin(T41,S45)/β-catenin].  
 
o With respect to effects on cell cycle and growth we saw marked reduction in p21, an 
increase in p53 and MDM2 (S166), slight reduction in CDK1, cyclin D1, and reduction 
of Elk1 (S383). No effects were seen for pChk1 (S296, S345)/Chk1, pChk2(T68)/Chk2, 
pRB(S807,S811)/RB, p16INK4A, pP27KIP1(T157)/P27KIP1, PCNA, cyclin B, cyclin E1, or 
MIG6. No effects were seen on c-Myc, ETS1, or JNK (T183, Y185). 
 
o With respect to effects on cell adhesion and motility we saw marked reduction in 
pFAK(Y397)/FAK, reduction in collagen VI, increase in myosin IIa (S1943), and slight 
increase in P-cadherin and paxillin. No changes were seen in β-actin, tau, α-tubulin, 
CK19, N-cadherin, E-cadherin, fibronectin, MMP2, or myosin11. 
 

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2.3.2 Role of ITK in Melanoma; In Vivo 
 
The effect of ITK inhibition on in vivo growth was tested in human melanoma xenografts 
established from melanoma cell lines that were expressing high levels of ITK.  BI 10N treatment 
(15mpk, administered in medicated chow) significantly slowed melanoma growth in both ITK-
high expressing human melanoma xenografts without any signs of toxicity (lethargy, weight 
loss). Treatment of the ITK-high expressing Tyr-CRE-ERT2 B-RafCA PtenL/L genetically 
engineered murine model (GEMM) with BI 10N significantly reduced melanoma growth and 
prolonged survival, whereas no such effect was seen with the non-ITK expressing Tyr-
HRasG12VInk4a/Arfnull. To investigate the mechanism of action of BI 10N in vivo, tumors were 
stained with cyclin D2, a marker of cell proliferation and LC3, a marker of autophagy by IHC. In 
BI 10N-treated tumors, cyclin D2, but not LC3, was significantly decreased (Carson et al., 
2015). 
 
 
2.3.3 Immunomodulatory Role of ITK in Melanoma  
 
Several lines of evidence by us and others suggest that ITK may also play an immunomodulatory 
role in melanoma. UNC-CH served as the hub to perform RNAseq and analysis of melanoma 
samples as part of The Cancer Genome Atlas Project (TCGA). Unsupervised clustering of 329 
untreated melanoma samples using the top 1,500 genes with the maximum absolute deviation 
identified three RNAseq clusters defined as ‘immune-high’ (n=168, 51%), ‘keratin-high’ (n=102, 
31%), and ‘microphthalmia-associated transcription factor (MITF)-low’ (n=59, 18%) based on 
gene function of discriminatory mRNAs (Cancer Genome Atlas Network (2015)). The ‘immune-
high’ cluster is comprised of genes associated with various immune cell subsets (T cells, B cells, 
NK cells), immune cell signaling (for B-cells, T-cells, or non-immune cell subset-specific), 
various immune checkpoint proteins, soluble factors and receptors, as well as melanoma 
antigens. In other words, this sample cluster reflects melanomas with an ‘inflamed’ signature, as 
previously described (Gajewski et al., 2013). Among the mRNA that comprised the ‘immune-
high’ cluster was significantly overexpressed ITK [Figure 1 and The Cancer Genome Atlas 
Network (2015)].  

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Given the role of ITK in 
distinct immune cell subsets, 
we have examined ITK 
expression in Ficoll-separated 
PBMCs obtained from patients 
with end-stage metastatic 
cutaneous melanoma and 
healthy human subjects. We 
optimized our anti-ITK 
antibody (ab32039) for flow 
cytometry, as there has not 
been a report to date about 
assessment of ITK expression 
in PBMC by flow cytometry. 
Figure 2 shows expression of 
ITK protein in Ficoll-isolated 
PBMC obtained from a 
representative normal subject. 
The mean percentage of ITK+ 
FSClow/SSClow cells among 
normal subjects was 51%. More than 50% of CD3+CD8+ and CD3+CD4+ were found to be ITK-
positive (data not shown). Analysis of PBMCs obtained from patients with metastatic melanoma 
showed that the expression of ITK was highly variable, but not lower than ITK levels in normal 
human subjects. Peripheral blood from 3 of 5 subjects with distant metastatic cutaneous 
melanoma was collected several weeks after the initiation of a BRAF inhibitor-based therapy. In 
these patients, ITK expression was significantly higher than the expression of ITK in normal 
subjects. Given the data regarding activation of tumor-infiltrating lymphocytes (TILs) in 
response to vemurafenib (Koya et al., 2012) and the increased infiltration of tumors by CD8+ 
cells as early as 15 days after BRAF inhibition treatment (Wilmott et al., 2012; Frederick et al., 
2013), we postulate that the higher expression of ITK in PBMC from patients who were recently 
started on BRAF inhibitors may reflect direct or indirect (i.e. compensatory) responses to direct 
activation of immune cells by BRAF inhibitors. These data as well as other reports describing the 
role of ITK in type 2 T helper cells (Dubovsky et al., 2013; Gunderson et al., 2016; Stiff et al., 
2016), which do not favorably contribute to antitumor response in melanoma (Tatsumi et al., 
2002), suggest that ITK inhibition may possibly have an additional immunomodulatory role. In 
addition, ibrutinib via its effect on BTK may also have an immunomodulatory role towards 
myeloid-derived suppressor cells (Stiff et al., 2016), B-cells and tumor associated macrophages 
(Gunderson et al., 2016).  In fact, preclinical models have shown synergy in antitumor response 
when ibrutinib is combined with inhibitors of the PD-1/PD-L1 pathway (Sagiv-Barfi et al., 
2015). The clinical significance of these findings is currently being explored in an early phase 
clinical trial of ibrutinib with corresponding inhibitors of the PD-1/PD-L1 pathway 
(NCT02403271, NCT02401048). 
 
 
 

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Figure 
2. 
Flow cytometric analysis of PBMC for total ITK expression. A. Gating strategy using forward scatter 
(FSC) and side scatter (SSC) parameters in a normal subject. Cells with low FSC/SSC features (e.g. 
lymphocytes) express ITK (red histogram) approximately 1-log difference higher than isotype control (blue 
histogram) and/or unstained cells (black histogram). B Expression of ITK in PBMCs from patients with 
metastatic melanoma. Abbreviations. B, BRAF; N, NRAS; mut, mutant; Tx, treatment; D, dabrafenib; T, 
trametinib; I, ipilimumab; inf, infusion; wt, wild type. 
 
2.3.4 Activity Against ITK 
 
In addition to the data on ibrutinib’s inhibition of the ITK summarized in Section 2.2.1.1, a 
number of published reports also document this inhibition (Honigberg et al., 2010; Dubovsky et 
al., 2013). In fact, ibrutinib is an inhibitor of a large number of Tec and Src/Abl family kinases in 
addition to ITK. Table 2 summarizes tyrosine kinases that have the highest affinity (IC50 
<25nM) with ibrutinib, the number of melanomas that were stained positive for a particular 
tyrosine kinase over the total number of stained melanomas, as part of the Human Protein Atlas 
(*,www.proteinatlas.org), as well as the potential biologic role of these kinases in melanoma 
biology, based on peer-reviewed publications. From this table it is notable that HER4, YES, Csk, 
EGFR, and HER2 have been previously described to have a role in melanoma. We propose that 
the expression status of each of these 5 proteins in archived or freshly collected (immediately 
prior to enrollment to this study) FFPE tumor tissues should be investigated as potential 
mediators of antitumor response to ibrutinib. 
 
Table 2.  High-affinity ibrutinib targets and their relevance to melanoma 
Targets 
IC50 
(nM)§ 
Expression in Melanoma 
Biological Role in Melanoma 
BTK 
0.39 
11/32* 
Unkn 
ErBB4/HER4 0.64 
18/23* 
(Tworkoski et al., 2011) 
Blk 
0.94 
2/11* 
Unkn 
Bmx/Etk 
1.1 
12/21* 
Unkn 
Fgr 
2.86 
11/11* 
Unkn 
Txk 
2.87 
1/12* 
Unkn 
Lck 
3.49 
2/24* 
No direct role 
Yes 
3.92 
18/24* (Loganzo et al., 1993; 
Lee et al., 2010; Liu et al., 2012) 
(Marchetti et al., 1998; Liu et al., 2012) 

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To assess the in vitro effect of ibrutinib in melanoma cell lines that express ITK at various levels, 
we treated melanoma cells with increasing concentrations of ibrutinib (up to 50nM). Figure 3 
shows proliferation rates for melanoma cell lines expressing ITK at various levels. Proliferation 
of two of the three high-ITK expressing, but none of the intermediate or low-ITK expressing 
melanoma cell lines, was completely suppressed when ibrutinib was administered at 
concentrations as low as 5nM, which is comparable to the ibrutinib levels that have been 
previously shown to inhibit various cell lines prepared from patients with various B-cell 
malignancies (Zheng et al., 2014).  
 
Fluorescent immunocytochemical analysis for protein expression levels of other putative 
ibrutinib targets (TXK, BMX, TEC, BTK, c-FGR, YES, HCK, ERBB4, EGFR, Table 3) in these 
melanoma cell lines show that the ibrutinib effect is probably not mediated via TXK, BMX, 
TEC, BTK, and HCK whereas c-FGR, YES, ERBB4, and EGFR may play some role solely on 
the basis of expression by melanoma cells. We will name the first group of tyrosine kinases as 
“low priority” ibrutinib targets for melanoma and will name the latter group as “high priority” 
ibrutinib targets for melanoma. The protein expression status of the “high priority” ibrutinib 
targets will be systematically investigated in archived or freshly collected (immediately prior to 
enrollment to this study) FFPE tumor blocks that will be collected at baseline from the subjects 
who will participate in the study. These results indicate that ibrutinib exerts its anti-proliferative 
effect via suppression of ITK, although other, yet unidentified targets may also be involved (e.g. 
ErbB2/Her2, Csk). 
 
Tec 
5.49 
12/12* 
Unkn 
Csk 
6.17 
6/33* (Lee et al., 2010) 
(O'Connor et al., 1995; Perez et al., 2001; 
Niu et al., 2002; Hwangbo et al., 2010; 
Gallagher et al., 2013) 
EGFR 
7.8 
5/35* (Mattei et al., 1994; 
Katunaric et al., 2014) 
(Tworkoski et al., 2011; Girotti et al., 
2013; Sun et al., 2014) 
Brk 
10.1 
30/33* (Easty et al., 1997) 
Unkn 
ITK 
11.7 
 (91%) 
(Carson et al., 2015) 
Hck 
16.98 
11/12 
Unkn 
ErbB2/HER2 
21.57 
10/33* (Kluger et al., 2004; 
Mirkina et al., 2014) 
(Zhang et al., 2013) 

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Figure 3. Effect of ibrutinib on proliferation rate of high- (HI), intermediate- (INT), and low (LO)-
ITK expressing melanoma cell lines. Cells were added to 10 cm2 6-well dishes at a density of 50,000 
cells per well. Ibrutinib was added in DMSO, which was used as a drug vehicle control. Cells were 
harvested using trypsin (0.025%) in PBS solution (R-001-100, Gibco) containing 0.01% EDTA for 
approximately 5 min. Cells were counted using the Countless Automated Cell Counter (C10227, Life 
Technologies). 
 
Table 3. Non-receptor tyrosine kinase expression levels in melanoma cell lines by single 
color fluorescent immunocytochemistry* 
Itk** 
Txk 
Bmx 
Tec 
Btk 
c-Fgr 
Yes 
Hck 
ErbB4 
EGFR 
SKMel 153 
4941 
82 
39 
20 
12 
136 
203 
12 
106 
17 
RPMI 8322 
193 
56 
27 
18 
6 
73 
120 
11 
47 
1 
VMM39 
264 
50 
40 
27 
25 
100 
163 
23 
80 
1 
PMWK 
31 
55 
37 
18 
11 
68 
148 
18 
56 
162 
SKMEL103 
36 
54 
36 
27 
36 
78 
185 
20 
74 
79 
A375 
44 
63 
41 
24 
17 
70 
160 
11 
76 
83 
*Units for data are arbitrary immunofluorescence (IF) units taking background intensity into account 
**Data included in (Carson et al., 2015) 
Antibody sources are: ITK (Abcam, ab32039); TXK (Acris Antibodies, AP14483PU-N); BMX (Novus 
Biologicals, NBP1-19437), TEC (Abcam, ab32368), BTK (Novus Biologicals, NBP1-00728), c-Fgr 
(Biorbyt, orb160411), Yes (Proteintech, 20243-1-AP), HCK (Proteintech, 11600-1-AP), ErbB4 
(Millipore, 05-1133), EGFR (Zymed/Invitrogen, 28-0005) 
 
The rationale for treatment of melanoma with ibrutinib is based on in vitro and in vivo data 
highlighting the potential important direct antitumor effect of ITK suppression in melanoma, and 
perhaps on its possible role as an immunomodulating agent in this disease. 
 
Based on the data just outlined, we hypothesize that ibrutinib will demonstrate clinical activity 
against melanoma as evidenced by an improved antitumor OR and prolonged PFS compared to 
historical data in patients with disease refractory to immune checkpoint inhibition and (in those 
with BRAF600 mutant disease) MAPK inhibition (Ribas et al., 2015; Weber et al., 2015).  
 

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2.4 Rationale for 840 mg dose of Ibrutinib 
 
Table 2 shows that the IC50 for ITK (as well as other ibrutinib targets with interest in melanoma 
and other solid tumors, such as EGFR and HER2) over BTK is 30-fold higher. However, the 
concentrations required for enzymatic inhibition in cells and inhibition of cellular growth of 
sensitive cell lines in vitro, is similar to or only slightly higher than required for BTK. When 
ibrutinib was tested at 420mg dose in patients with CLL only up to 70% ITK occupancy was 
achieved; in contrast, >90% BTK occupancy was observed for that dose. Dedicated 
pharmacokinetic studies regarding ITK inhibition using ibrutinib do not exist, and are difficult to 
perform (downstream effectors of ITK signaling are different for different cell lines). However, 
from the IC50 studies, it can be inferred that a higher dose would be optimal for clinical 
indications where this target is mechanistically implicated. In addition, the slower-growing 
property of human tumors and the inherently less efficient penetration of a compound into solid 
tumor tissues may also contribute to the necessity for higher dose levels. In fact, ibrutinib at 
doses 840-1,400mg qd was administered for 28 days in normal individuals and did not have any 
serious side effects; the single dose AUC values corresponding to the 840mg dose was 
1,445±869 ng ⋅ hr/mL, which is approximately 50% greater than steady-state exposures seen at 
the highest indicated dose (560 mg; see ibrutinib package insert). At this time there are safety 
and efficacy data only for the 420mg and 840mg in the dose escalation study of ibrutinib in 
patients with CLL, which are equivalent for both doses (Byrd et al., 2013). Due to the expected 
heterogeneity in the sensitivity profile of clinical cancers and patient pharmacokinetics, a starting 
dose of 840 mg/day has been selected for this study with allowance for dose de-escalation. 
 
2.4.1 Safety, Pharmacokinetics and Efficacy of 840 mg dose 
 
Safety, pharmacokinetics and efficacy data are emerging from ongoing Phase I studies of 
ibrutinib in patients with lymphoma given 840mg po qd. Briefly, in a study by Dunleavy et al. 
(NCT02203526), 14 patients with central nervous system (CNS) lymphoma received ibrutinib in 
cohorts (560, 700, and 840 mg pd qd) for 14 days prior to cycle 1, followed by dose-adjusted 
TEDDI-R with ibrutinib every 21 days for 6 cycles.  Four patients have been treated with 840mg 
po qd of ibrutinib; and no DLTs were reported at this dose. Notably, higher ibrutinib doses 
achieved higher levels in cerebrospinal fluid (CSF) and longer times above the IC50; median 
time above the IC50 was 4 hours after 560 mg and 8.5 hours after 700 mg doses of ibrutinib were 
given. CSF penetration corrected for protein binding was 21.4-100% for ibrutinib and 48-120% 
for its metabolite. Eleven patients were evaluable for response to ibrutinib alone with 10 partial 
responses and 1 stable disease reported (Dunleavy et al., 2015).   
 
Grommes et al. (NCT0232315326) are investigating single-agent ibrutinib in relapsed/refractory 
primary or secondary CNS lymphoma (PCNSL, N=10) in an ongoing Phase I trial.  PK studies 
have shown ibrutinib penetrates the CNS and has activity in PCNSL. Seven patients have 
received the 840 mg dose.  Higher CSF drug concentrations were achieved and higher drug 
concentrations were found in CSF after 840 mg ibrutinib. Toxicity data were reported in the first 
6 patients enrolled and 2 subjects experienced grade 4 neutropenia and lymphopenia that 
resolved after ibrutinib was withheld.  Thus far, ibrutinib (840 mg) has proven to be tolerable 
when given as monotherapy or in combination with intensive chemotherapy (Grommes et al., 
2015). 

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2.5 Correlative Studies Background 
 
See Sections 2.3.1 thru 2.3.4 for detailed background information on the biomarkers to be 
evaluated in this study. In addition to our primary hypothesis related to the clinical activity of 
ibrutinib, we also hypothesize that increased expression of ITK will be associated with increased 
antitumor RR and prolonged PFS. However, we cannot exclude that high protein expression of 
other putative ibrutinib targets in archived or freshly collected (immediately prior to enrollment 
to this study) FFPE tumor tissues, in particular HER2, HER4, YES, CSK, EGFR, cFGR, may not 
have a role in predicting response to ibrutinib in metastatic cutaneous melanoma, independent of 
or in combination with ITK. Finally, we hypothesize that ibrutinib will not show any inhibitory 
effect on host immune response; rather it may have beneficial effects on host immune response 
by reversing melanoma-mediated Th2-bias (Tatsumi et al., 2002).  
 
To address our correlative objectives, expression of ITK and 6 other putative ibrutinib targets 
will be assessed on archived or freshly collected (immediately prior to enrollment to this study) 
FFPE tumor blocks. Given the higher sensitivity and specificity of IF, the expression of the exact 
same proteins (ITK and other putative ibrutinib targets) could also be assessed in melanoma cells 
(S100+) using 2-color IF, if additional tumor sections are available. Analysis of the staining data 
by IF will be performed by Aperio imaging, as we have previously published (Schlegel et al., 
2013; Nikolaishvilli-Feinberg et al., 2014; Carson et al., 2015).  Flow cytometry will be 
performed on PBMC collected at three different time points (prestudy treatment, day 29 (i.e., 
predose day 1 of cycle 2), and at disease progression) for analysis of immune regulatory cell 
populations as well as markers for Th1 and Th2 responses [i.e. regulatory T cells, myeloid-
derived suppressor T cells, Th1/Th2 ratio, anergic (PD1±, TIM3±, CTLA4±), and CD8+ effector 
cells]. 
 
3. PATIENT SELECTION 
 
3.1 Inclusion Criteria  
 
Patients must meet all of the following inclusion criteria to participate in this study: 
 
3.1.1 Histologically confirmed melanoma of cutaneous primary; metastatic melanoma from 
unknown primary are allowed because melanoma of unknown primary is biologically similar 
to cutaneous melanomas (Egberts et al., 2014). 
  
3.1.2 Measurable disease, defined as at least one lesion that can be accurately measured in at 
least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers by clinical exam.  
See Section 11 for the evaluation of measurable disease. 
 
3.1.3 Stage IV disease. 
 

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3.1.4 If BRAFV600-mutant, documented refractory disease to at least one BRAF inhibitor 
(dabrafenib or vemurafenib) and/or a MEK inhibitor (trametinib or cobimetinib), defined as 
progression of measurable disease as per RECIST 1.1 criteria while on treatment.  Subjects 
with MAPK inhibitor-intolerance are eligible if they meet criteria outlined in inclusion 
criterion 3.1.21. 
 
3.1.5 Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined as disease 
progression following at least 2 infusions of the same drug. Radiographic disease progression 
will be documented by the institutional radiologist  based on any radiographic evidence (MRI, 
CT, PET, or other modalities, etc.) of disease progression on two separate radiographic scans 
assessment obtained at least 4 weeks apart. This minimum 4-week interval is required to define 
PD-1 inhibitor resistance based on imaging. Alternatively, Clinical Disease Progression may be 
documented on examination by the treating investigator.  
 
 
3.1.6  Prior treatment-related toxicity resolved to ≤ Grade 1 or baseline with the exception of 
alopecia and permanent grade ≤2 toxicities related to prior immune checkpoint inhibitor 
treatment (e.g. PD-1/PD-L1, CTLA-4, CD40, LAG3) treatment with the review and 
approval by the Lead PI. 
 
3.1.7 Prior radiation allowed (no restriction on amount); measurable lesion(s) may not have 
been previously irradiated. 
 
3.1.8 Males or female subjects age ≥18 years.   
 
Because no dosing or adverse event data are currently available on the use of ibrutinib in 
patients <18 years of age, children are excluded from this study, but will be eligible for 
future pediatric trials. 
 
3.1.9 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.10 Life expectancy of greater than 3 months. 
 
3.1.11 Patients must have normal organ and marrow function as defined below: 
 
Hemoglobin 
≥9.0g/dL 
Absolute neutrophil count (ANC) 
>1,500/µL 
Platelets  
>100,000/µL 
AST (SGOT)/ALT (SGPT) 
≤2 x upper limit of normal (ULN);  
≤5 x ULN, if liver metastasis 
Total bilirubin 
≤1.5 x ULN (unless Gilbert’s syndrome of  
disease infiltration of the liver is present 
Creatinine clearance 
Estimated GFR ≥30mL/min/1.73m2  
(Cockcroft-Gault) 
 

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3.1.12 Patients with brain metastases are allowed provided that: 
• No leptomeningeal disease is present, 
• Intracranial disease is controlled by prior local therapies (craniotomy, stereotactic 
radiosurgery, whole brain irradiation), as evidenced by brain MRI 4 weeks post treatment 
indicating no new intracranial disease, 
• Stable or decreasing dose of steroids provided patient on ≤ 20mg of prednisone or its 
equivalent daily. 
 
3.1.13 Given the effects of ibrutinib on platelet aggregation, ibrutinib should be held at least 3 to 
7 days pre- and post-surgery, depending upon the type of surgery and risk of bleeding.  
Please see Section 5.2.5 for definitions of major and minor surgery. 
 
3.1.14 The effects of ibrutinib on the developing human fetus are unknown.  For this reason and 
because tyrosine kinase inhibitors may be teratogenic, women of child-bearing potential 
and men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of study participation and for 90 
days after completion of ibrutinib administration.  Should a woman become pregnant, or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.  Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 90 days after completion of ibrutinib administration. 
 
3.1.15 Negative serum pregnancy test within 7 days of treatment initiation with ibrutinib in 
women of childbearing potential (WOCBP). 
 
3.1.16 Ability to swallow oral medications. 
 
3.1.17 Patients with autoimmune disease requiring systemic corticosteroid treatment (and 
previously ineligible to receive systemic immunotherapies for melanoma) are allowed on 
condition that they do not receive more than 20mg of daily dose methylprednisolone, 
prednisone, or its equivalent. This does not include autoimmune diseases caused by previous 
immunotherapy treatments for melanoma that require ongoing treatment with corticosteroids 
(e.g. autoimmune colitis or autoimmune hepatitis receiving corticosteroids).  
 
 
3.1.18 Willing to consent to allow access to known archival tumor tissue [NOTE: designated 
pathologist from participating site OR Lead Principal Investigator must sign-off to ensure 
“sufficient” tumor should be available for support of tumor imaging studies (multi-color 
immunofluorescence)]; See Appendix B for a sample of the sign-off letter from 
pathologist and see Section 9.3.1.1 for process of Lead Principal Investigator to provide 
sign-off that there is sufficient archival tissue. 
 

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3.1.19 If archival tumor tissue from a metastatic melanoma lesion is unavailable OR designated 
pathologist from participating site cannot sign-off to ensure that “sufficient” tumor is 
available from existing archival tumor block for support of tumor imaging studies (see 
Appendix B for a sample of the sign off letter), patients must be willing to consent to 
undergo a biopsy to collect metastatic tumor tissue. Collection of fresh biopsy tissue 
does not guarantee enrollment, unless the pathologist from the participating site signs-
off that “sufficient” tumor has been collected. 
 
3.1.20 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.21 Subjects who are unable to tolerate BRAF inhibitor and/or MEK inhibitor therapy due to 
grade ≥2 toxicity (CTCAE v5.0) from these agents, irrespective of antitumor response, 
are eligible on condition that: (a) toxicities persisted despite change from doublet to 
singlet therapy (i.e. from concurrent BRAF inhibition plus MEK inhibition to BRAF 
inhibition alone), (b) toxicities are attributed to a class effect, and therefore switch from 
one drug to another is expected to induce the same type of toxicity (e.g. ocular toxicities 
or cardiac dysfunction from MEK inhibitor), (c) drug-specific toxicities that do not 
resolve with switch from one BRAF inhibitor to another (i.e. dabrafenib to vemurafenib, 
or vice versa), will be eligible for enrollment in 9922. In other words, patients will be 
allowed to enroll into the NCI9922 study despite lack of progression to MAPK inhibitor 
treatments, on condition that grade 2 or higher toxicities attributed to MAPK inhibitors 
resolve to grade 1, or less, at the time of study enrollment. 
 
3.2 Exclusion Criteria 
 
Subjects meeting any of the criteria below may not participate in the study: 
 
3.2.1 Patients with melanoma of mucosal or ocular primary.  
 
3.2.2 Patients who have had chemotherapy or immunotherapy within 4 weeks (6 weeks for 
      nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to Cycle 1 Day 1.  
Patients who have had tyrosine kinase inhibitors (such as Braf or MEK inhibitors) within 15 
days of Cycle 1 Day 1. 
 
3.2.3 Patients who are receiving any other biologic, cytotoxic or investigational agents. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ibrutinib (difficulty breathing, lip swelling, itching or rash). 
  
3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.6 Pregnant and breastfeeding women are excluded from this study. 
 
• Pregnant women are excluded in this study, because ibrutinib is a tyrosine kinase 

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inhibitor with 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 with ibrutinib, breastfeeding should be 
discontinued if the mother is treated with ibrutinib.   
 
3.2.7 HIV-positive patients on combination antiretroviral therapy are eligible; unless the 
patient’s CD4+ count is below the institutional lower limit of normal. 
 
3.2.8 Uncontrolled autoimmune hemolytic anemia or ITP resulting in (or as evidenced by) 
declining platelet or Hgb levels within the 4 weeks prior to first dose of study drug. 
 
3.2.9 Presence of transfusion-dependent thrombocytopenia. 
 
3.2.10 Need for daily corticosteroids at high doses (prednisone ≥20 mg daily, or an equivalent) 
is prohibited from 28 days prior to first dose and during treatment with ibrutinib. Brief 
(up to 7 days) and episodic use of systemic corticosteroids for other general conditions 
(e.g. pre-medication for radiographic imaging due to IV contrast allergy, COPD 
exacerbation, poison ivy, etc.) is allowed. 
 
3.2.11 Prior exposure to ibrutinib or other ITK inhibitors. 
 
3.2.12 History of prior malignancy, with the exception of the following: 
• Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of 
the cervix, 
• Prostate cancer not under active systemic treatment other than hormonal therapy and 
with documented undetectable PSA (<0.2ng/mL), 
• CLL/SLL provided patient has isolated lymphocytosis (Rai stage O), and does not 
require systemic treatment [for “B” symptoms, Richter’s transformation, lymphocyte 
doubling time (<6 months), lymphadenopathy or hepatosplenomegaly], 
• Lymphoma of any type or hairy-cell leukemia provided patient is not on active 
systemic treatment and is in complete remission, as evidenced by PET/CT scans and 
bone marrow biopsies for at least 3 months, 
• History of malignancy provided that patient has completed therapy and is free of 
disease for ≥ 2 years. If patient had other malignancy within the last 2 years from 
which he may have been completely cured by surgery alone, he may be considered to 
be enrolled on condition that the risk of development of distant metastatic disease 
based on AJCC staging system is less than 30%. 
 
3.2.13 Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease, as defined by the New 
York Heart Association Functional Classification, or history of myocardial infarction within 
6 months prior to first dose with study drug. 
 

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3.2.14 Unable to swallow capsules, or disease significantly affecting gastrointestinal function 
and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of 
portions of small bowel larger than 3 feet, or poorly controlled inflammatory bowel 
disease affecting the small intestine.  
 
3.2.15 Known serologic status reflecting active hepatitis B or C infection.  Patients that are 
hepatitis B core antibody positive, but antigen negative, will need a negative polymerase 
chain reaction (PCR) prior to enrollment.  [NOTE: Hepatitis B antigen or PCR positive 
patients will be excluded.] 
 
3.2.16 History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
  
3.2.17 Current life-threatening illness, medical condition, or organ system dysfunction, which, 
in the Investigator’s opinion, could compromise the patient’s safety, or put the study at 
risk. 
 
3.2.18 Received anticoagulation therapy with warfarin, or equivalent vitamin K antagonists, 
within the last 28 days prior to day 1 of ibrutinib. Patients with familial coagulopathic 
diseases (e.g. hemophilia, von Willebrand disease) are also excluded. If applicable, 
subjects must discontinue fish oil and vitamin E supplements within 7 days prior to 
initiating ibrutinib therapy.   
 
3.2.19 Subjects with known hepatic insufficiency [i.e. Child-Pugh Score A (mild), Child-Pugh 
Score B (moderate) or Child-Pugh Score C (severe)] according to Child-Pugh Criteria 
(See Appendix F). 
 
3.2.20 Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior 
to the first dose of ibrutinib or subjects who require continuous treatment with a strong 
CYP 450 3A inhibitor.  
 
3.3 Inclusion of Women and Minorities 
 
NIH policy requires that women, members of minority groups, and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research, unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. See Section 13.2 for details 
on projected enrollment. 
 
 

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4. REGISTRATION PROCEDURES 
 
4.1 Investigator and Research Associate Registration with CTEP 
 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list 
all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
For questions, please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 

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Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm>. 
 
 
 
4.2 Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9922 protocol page located on the CTSU 
Web site.  Permission to view and download this protocol is restricted and is based on person and 
site roster data housed in the CTSU RSS.  To participate, Investigators and Associates must be 
associated with the Corresponding or Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 

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34 
• Click on the By Lead Organization to expand, then select LAO-NC010, and protocol # 
9922. 
• Click on LPO Documents, select the Site Registration documents link, download and 
complete the forms provided.  (NOTE: For sites under the CIRB initiative, IRB data will 
load to RSS as described above.) 
 
4.2.2 Requirements for 9922 Site Registration 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or combination is accepted) 
• Study Chair Approval – Protocol training 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.   
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000  
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 

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35 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
 
4.3 Patient Registration 
 
In cooperation with the Corresponding Organization (Duke Cancer Institute LAO), the Lead 
Protocol Organization or LPO (University of North Carolina at Chapel Hill) is utilizing an online 
‘study portal’ for key study communication from participating sites to the Lead Principal 
Investigator and Study Coordinator. The study portal operates through REDCap, a secure, web-
based application, managed by the Duke Cancer Institute LAO.  Participating sites will not 
require REDCap user accounts or passwords to access the study portal for this study.   
 
The 9922 Study Portal may be accessed through the following link: http://j.mp/2eup4yF. 
Additional information about study portal use is available in LPO Documents for the study on 
www.ctsu.org. 
     
Prior to registering patients into Oncology Patient Enrollment Network (OPEN), participating 
sites are instructed to access the 9922 Study Portal for the following: 
 
• Subject Consent – Within 24 business hours of subject signing consent for the study, the 
Site Coordinator accesses the study portal to upload consents and notify the Study 
Coordinator of subject consent.  Upon receipt of consent notification, the Study 
Coordinator will email the Site Coordinator with a subject screening ID number.  
 
• Pathology Confirmation – Subject eligibility requires confirmation that the patient has 
“sufficient” tumor available for support of tumor imaging studies.  The Site Coordinator 
will confirm the subject has sufficient tumor by one of the following processes: 
 
a) Pathologist at the participating site reviews available tissue and provides a signed 
letter (refer to Appendix B for sample letter).  The Site Coordinator uploads the 
letter to the study portal.  The Study Coordinator will email the Site Coordinator 
to confirm receipt of letter. 
 
b) Lead Principal Investigator reviews pathology reports, stained slides, and/or 
digital images provided by the participating site (refer to Section 9.3.1.1 for 
further instructions).  The Site Coordinator ships and/or emails de-identified 
materials to the Lead Protocol Organization or LPO (University of North Carolina 
at Chapel Hill).  After review and determination of sufficient tumor by the Lead 
Principal Investigator, the Study Coordinator will email the Site Coordinator 
regarding the outcome of the pathology review. 
 
• Eligibility Confirmation – After completion of all screening evaluations and if possible, 
within at least 48 business hours of anticipated study treatment start, the Site Coordinator 
accesses the study portal to upload completed eligibility checklist and de-identified 

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supporting source documentation including sufficient tumor tissue pathology 
confirmation documentation. After review of eligibility documents by the Lead Principal 
Investigator or designee(s), the Study Coordinator will email the Site Coordinator with 
confirmation or questions/comments regarding subject eligibility.  If eligibility is 
confirmed, the Site Coordinator will be instructed by the Study Coordinator via email to 
proceed to patient registration in OPEN. 
 
4.3.1 
OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available to users on a 24/7 basis.  It is integrated with 
the CTSU Enterprise System for regulatory and roster data interchange and with the Theradex 
Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment.  Patient enrollment data entered by Registrars in OPEN/IWRS will automatically 
transfer to the NCI’s clinical data management system, Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 
OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients: Be on an ETCTN Corresponding or Participating Organization roster 
with the role of Registrar. Registrars must hold a minimum of an AP registration type. If 
a DTL is required for this study, the registrar(s) must also be assigned the OPEN 
Registrar task on the DTL. 
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated time frames.  
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
• Refer to additional instructions in Section 4.3. 
 
4.3.3 
OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.4 General Guidelines 
 
Following OPEN registration, patients should begin protocol treatment within 7 days.  Issues that 
would cause treatment delays should be discussed with the Lead Principal Investigator.  If a 
patient does not receive protocol therapy following registration, the patient’s registration on the 

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37 
study may be cancelled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
5. TREATMENT PLAN 
 
5.1 Agent Administration 
 
Ibrutinib treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
Treatment will consist of a fixed dose of 840mg of ibrutinib orally once daily on a continuous 
basis. For purposes of the study, treatment will be divided into 28-day treatment cycles, with 
treatment starting on Day 1 (D1) of Cycle 1.  
 
5.1.1 Ibrutinib 
 
Premedication for this agent is not required. 
 
Patients will be instructed on the following: 
• Take each dose of ibrutinib capsules (six 140 mg capsules = 840mg) once daily by 
mouth. 
• Swallow the capsules whole with water [use a glass (8 ounces, 1cup) of water total for 
each 840mg dose]. 
• Take each dose at approximately the same time each day. 
• Ibrutinib must not be taken with grapefruit juice. Patients should avoid drinking 
grapefruit juice while on this study. 
• Do not open, break or chew capsules, and do not attempt to dissolve them in water. 
• Each dose, along with the date and time, must be recorded on a medication diary 
provided to you at the beginning of the study. Bring the diary with you to each study 
visit and return the diary to research staff, as per study instructions. 
• 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. Extra capsules should 
not be taken to make up for the missed dose.  
• If you vomit immediately after taking your dose, do not replace this dose. Continue 
dosing the next day, as per usual. Record the vomiting episode on your medication diary.  
• Return any remaining ibrutinib capsules to research staff once treatment is complete, and 
as per study instructions. 
• Do not take fish oil and vitamin E supplement while on this study. 
 
5.1.2 Other Agent(s) 
 
N/A 
 

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5.1.3 Other Modality(ies) or Procedures 
 
N/A 
 
5.2 General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of ibrutinib with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes.  Appendix D presents guidelines for identifying 
medications/substances that could potentially interact with the study agent(s). 
 
 
 
5.2.1 CYP Inhibiting/Inducing Drugs 
 
Ibrutinib is metabolized primarily by CYP3A4. Avoid co-administration with strong CYP3A4 
(e.g., 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, 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 140 mg (for 
840 mg/day dose, reduce to 280 mg) for the duration of the inhibitor use. No dose adjustment is 
required in combination with mild inhibitors. Avoid grapefruit and Seville oranges during 
ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A. 
 
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, 
and St. John’s Wort). Consider alternative agents with less CYP3A induction. 
 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please 
refer to the current version of the IB. A more frequently updated list of inhibitors and inducers is 
available at http://medicine.iupui.edu/CLINPHARM/ddis/main-table 
  /.Appendix D is a guideline for patients regarding medications/substances that could potentially 
interact with the ibrutinib study agent(s).  Refer to the Ibrutinib IB for a comprehensive list of these 
agents. 
  
5.2.2 QT Prolonging Agents 
 
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with ECGs and electrolytes should be considered and, if needed, the Medical 
Monitor may be contacted. See https://www.crediblemeds.org/ for a list of medications 
associated with QTc prolongation. 
 
5.2.3 Antiplatelet Agents and Anticoagulants 
 

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39 
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 
(e.g. aspirin, clopidrogel, non-vitamin K antagonist oral anticoagulants). Subjects with 
congenital bleeding diathesis have not been studied.  
 
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. 
 
 
 
5.2.4 Prohibited Medications 
 
In addition to the above considerations, any non-study chemotherapy, anticancer immunotherapy 
as well as corticosteroids (at dosages equivalent to prednisone ≤20mg/day), experimental 
therapy, or radiotherapy are prohibited. 
 
5.2.5 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 emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
 
5.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Patient decides to withdraw from the study, 

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• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator, or 
• Death 
 
5.4 Duration of Follow Up 
 
Patients will be followed for up to 2 years post discontinuation of ibrutinib or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
 
 
 
5.5 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 Ibrutinib 
 
Dose Escalations of Ibrutinib 
No intra-subject dose escalation of ibrutinib is permitted.   
 
Dose Delay 
Treatment with ibrutinib should be held for any unmanageable, potentially study drug-related 
toxicity that is grade 3, or higher, in severity.  If anticoagulation therapy is required, an 
anticoagulant other than warfarin or vitamin K antagonist must be used. Ibrutinib should not be 
re-started until the patient is clinically stable.   
 
Study drug may be held for a maximum of 14 days for neutropenia, and for 28 consecutive days 
for any other toxicity.  Study treatment should be discontinued if these limits are met and the 
patient followed up per protocol. 
 
If dose reductions of ibrutinib are required, please follow the guidelines provided in the table 
below. Ibrutinib should be permanently discontinued in patients who require <420 mg per day, 
and patients should be followed-up per protocol. The only exception to this rule will be patients 
on strong or moderate CYP3A inhibitors. If strong CYP3A inhibitor must be used, reduce 
ibrutinib dose to 140 mg, and if a moderate inhibitor must be used, reduce ibrutinib dose to 280 
mg for the duration of the inhibitor use (see section 5.2.1 for additional information). Subjects 
who develop hepatic insufficiency during the trial must discontinue ibrutinib therapy as 
described in the section below entitled Discontinuation of Ibrutinib for Patients with Hepatic 
Impairment. 
  

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Missed doses of ibrutinib are not to be made up.  In the event that ibrutinib dosing is interrupted, 
the duration of cycle/treatment will not be extended.  Therefore, if treatment is delayed on Day 1 
of a cycle due to toxicity, and the patient does not begin therapy until Day 5 (for example), the 
start date of drug for that cycle remains Day 5, not Day 1.  
 
Dose Level 
Ibrutinib Oral Daily Dose 
Number of 140mg Capsules 
-3 
420 mg 
3 
-2 
560 mg  
4 
-1 
700 mg 
5 
Starting Dose 1 
840 mg 
6 
 
If a patient experiences serious adverse events and there are conflicting recommendations, the 
investigator should use the recommended dose adjustment that reduces the dose to the lowest 
level. 
 
Dose Reduction and Discontinuation for Hematological Toxicities 
 
The actions in the table below should be taken for the following hematological toxicities. 
Investigator is allowed to take more conservative approaches at his discretion and clinical 
judgement, after discussing with Principal Investigator:  
• ANC <500/µL for >7 days (neutrophil growth factors are permitted per ASCO guidelines 
(Bennett et al., 1999; Smith et al., 2006) and use must be recorded in the electronic case 
report form (e-CRF). 
• A platelet count of <50,000/µL in the presence of grade 3 bleeding  
• A platelet count of <25,000/µL regardless of bleeding 
 
Ibrutinib Dose Delay and Dose Modifications for Hematological Toxicities 
Occurrence Action      
 
1st 
Holda ibrutinib until recovery to grade ≤1 or baseline; may resume at original 
dose level 
2nd 
Holda ibrutinib until recovery to grade ≤1 or baseline; resume at one dose level 
lowerb 
3rd 
Hold a ibrutinib until recovery to grade ≤1 or baseline; resume at one dose level 
lowerb 
4th 
Hold a ibrutinib until recovery to grade ≤1 or baseline; resume at one dose level 
lowerb 
5th 
Discontinue ibrutinib 
a Ibrutinib should be permanently discontinued and patients followed-up per protocol, if delay >28 days 
is required 
b If >3 dose reductions are required, ibrutinib should be permanently discontinued, and patient followed 
up per protocol. 
 
 
This same information is presented by specific hematological toxicity and grade in the tables 

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42 
below: 
 
Neutropeniaa 
Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 
No change in dose. 
Grade 4 lasting > 7 days  
 
(NOTE: do not reduce for 
neutropenia lasting < 7 
days) 
Holdb until ≤ Grade 1 or baseline, then: 
 
1st Occurrence: Resume at same dose level 
 
2nd Occurrence: Resume reduced by one dose level 
3rd Occurrence: Resume reduced by one dose level (again) 
4th Occurrence: Resume reduced by one dose levelc 
5th Occurrence: Permanently discontinue ibrutinib 
a Neutrophil growth factors are permitted per ASCO guidelines (Bennett et al., 1999; Smith et al., 
2006). Use of growth factors should be included in study data.  
bIbrutinib should be permanently discontinued and patients followed-up per protocol, if delay >14 days 
is required 
cIf >3 dose reductions are required, ibrutinib should be permanently discontinued, and patient followed 
up per protocol. 
 
Thrombocytopenia 
Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 with 
ongoing significant 
bleeding 
 
NOTE: if there is no 
ongoing significant 
bleeding, hold but do 
not dose reduce for 
Grade 3 
thrombocytopenia 
Holda until ≤ Grade 1 or baseline, then: 
 
1st Occurrence: Resume at same dose level 
2nd Occurrence: Resume reduced by one dose levelb 
3rd Occurrence: Resume reduced by one dose level (again) 
4th Occurrenece: Resume reduced by one dose level (gain)b 
5th Occurrence: Permanently discontinue ibrutinib 
Grade 4  
 
Holdb until ≤ Grade 1 or baseline, then: 
 
1st Occurrence: Resume at same dose level 
2nd Occurrence: Resume reduced by one dose level 
3rd Occurrence: Resume reduced by one dose level (again) 
4th Occurrence: Resume reduced by one dose level (again)b 
5th Occurrence: Permanently discontinue ibrutinib 
aIbrutinib should be permanently discontinued and patients followed-up per protocol, if delay >28 days 
is required 
bIf >3 dose reductions are required, ibrutinib should be permanently discontinued, and patient followed 
up per protocol. 
 

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43 
If therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should be held until 
the patient is clinically stable and has no signs of bleeding. Patients should be observed closely 
for signs and symptoms of bleeding. No dose reduction is required when study drug is restarted. 
 
Dose Reduction and Discontinuation for Non-Hematological Toxicities 
 
For the non-hematological events listed, only those which persist despite adequate 
treatment by the investigator’s/institution’s standards should be considered before 
hold/reduction of ibrutinib. 
 
 
Nauseaa, Vomitinga 
Diarrheab 
Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose.c 
Grade 3 
Holdd until ≤ Grade 1 or baseline, then: 
 
1st Occurrence: Resume at same dose level 
2nd Occurrence: Resume reduced by one dose level 
3rd Occurrence: Resume reduced by one dose level (again) 
4th Occurrence: Resume reduced by one dose level (again)e 
5th Occurrence: Permanently discontinue ibrutinib 
Grade 4 
Discontinue ibrutinib permanently a 
aRecommended management: anti-emetics 
bRecommended management: Loperamide antidiarrheal therapy; dosage schedule: 4mg at first onset, 
followed by 2mg with each loose bowel movement until diarrhea-free for 12 hours (maximum dosage: 
16mg/24 hours). Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
cIbrutinib may be withheld at the discretion of the investigator for grade 2 toxicity that is 
significantly impacting a patient’s quality of life.  
dIbrutinib should be permanently discontinued and patients followed-up per protocol, if delay >28 days 
is required. 
eIf >3 dose reductions are required, ibrutinib should be permanently discontinued, and patient followed 
up per protocol. 
 
Suspected pulmonary and/or CNS fungal infections 
• Investigators should be vigilant about detecting cases of suspected pulmonary and/or 
CNS fungal infections and, specifically, aspergillosis. 
• If a case of aspergillosis is suspected or observed in this trial, ibrutinib should be 
discontinued. 
• All suspected and confirmed cases of fungal infections should be reported to CTEP 
within 24 hours. 
 
Discontinuation of Ibrutinib for Patients with Hepatic Impairment 
 
Patients who develop mild, moderate, or severe hepatic impairment (ie, Childs-Pugh Class A, B 
or C, respectively) during the trial should permanently discontinue ibrutinib therapy and be 

NCI Protocol #: 9922 
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44 
removed from the study (Please refer to Appendix F for Childs-Pugh Scoring system of hepatic 
impairment).  
 
Any other 
Ibrutinib-related 
Adverse Event 
Management/Next Dose for Ibrutinib 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 
Holda until ≤ Grade 1 or baseline, then: 
 
1st Occurrence: Resume at same dose level 
2nd Occurrence: Resume reduced by one dose level 
3rd Occurrence: Resume reduced by one dose level (again) 
4th Occurrence: Resume reduced by one dose level (again)b 
5th Occurrence: Permanently discontinue ibrutinib 
Grade 4 
Discontinue ibrutinib permanently a 
aIbrutinib should be permanently discontinued and patients followed-up per protocol if delay >28 days 
is required 
bIf >3 dose reductions are required, ibrutinib should be permanently discontinued, and patient followed 
up per protocol. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AE (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 2082 patients. Below is the CAEPR for 
ibrutinib (PCI-32765). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 

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45 
7.1.1 CAEPRs for CTEP-supplied Agent 
 
7.1.1.1 CAEPR for Ibrutinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Ibrutinib (PCI-32765, NSC 748645) 
 
Frequency is provided based on 2082 patients. Below is the CAEPR for ibrutinib (PCI-32765). 
 
 
 
Version 2.5, May 25, 2017 
 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 4.0 Term) 
[n= 2082] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Blood and lymphatic system 
disorders - Other (leukostasis)2 
  
 
Febrile neutropenia 
 
  
 
 
Leukocytosis2 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
 
 
Ventricular tachycardia 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
 
 
Sudden death NOS 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection3 
  
 Infection3 (Gr 2) 

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46 
 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 4.0 Term) 
[n= 2082] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Infections and infestations - 
Other (bronchopulmonary and 
central nervous system 
infections)4 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
INVESTIGATIONS 
  
 
Lymphocyte count increased2 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased 
(Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
 
Hyperuricemia 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other (muscle 
spasms) 
 
  
 
Myalgia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (benign 
neoplasm of skin)5 
 
  
 
 
Treatment related secondary 
malignancy5 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
  
 
 
Peripheral sensory neuropathy   
 
 
Cognitive disturbance 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema)6 
  
 
Skin and subcutaneous tissue 
disorders - Other (rash)7 
 
 Skin and subcutaneous 
tissue disorders - Other 
(rash)7 (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
VASCULAR DISORDERS 
  

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47 
 
 Adverse Events with Possible  
 Relationship to Ibrutinib (PCI-32765) 
 (CTCAE 4.0 Term) 
[n= 2082] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Hypertension 
 
  
 
 
Hypotension 
  
 
Vascular disorders - Other 
(hemorrhage)8 
 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Leukostasis and/or leukocytosis have been observed especially in patients with chronic lymphocytic 
leukemia (CLL) and mantle cell leukemia (MCL). 
 
3Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
4Fungal infections especially respiratory tract infections due to aspergillus and/or pneumocystis and 
central nervous system (CNS) infections due to aspergillus have been observed in clinical trials of 
ibrutinib. These reports may include incidents of presumptive fungal infections based on response to anti-
fungal agents and/or radiographic evidence. 
 
5Other malignant diseases have been observed in patients who have been treated with ibrutinib including 
solid tumors, skin cancer, and hematological malignancies. 
 
6Angioedema may be seen in association with the immune-related adverse event of anaphylaxis. 
 
7Rash may include but not limited to the terms dermatitis, erythema, rash generalized, rash maculo-
papular, rash pustular, rash pruritic, and urticaria. 
 
8It is possible that treatment with ibrutinib may increase the risk of hemorrhage which may occur 
anywhere in the body including CNS hemorrhage (including but not limitied to Intracranial hemorrhage, 
Intraventricular hemorrhage, and Subdural hematoma), Ecchymoses, Purpura (petechia), Gastrointestinal 
hemorrhage (including but not limited to Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage), Genitourinary tract hemorrhage 
(including but not limited to Hematuria and Vaginal hemorrhage), Respiratory tract hemorrhage (including 
but not limited to Epistaxis), and Spontaneous hemorrhage. 
 
 
Adverse events reported on ibrutinib (PCI-32765) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that ibrutinib (PCI-32765) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemorrhagic diathesis); Blood and lymphatic system disorders - Other (lymphadenitis); Blood and 
lymphatic system disorders - Other (pancytopenia); Hemolysis 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block complete; Atrioventricular block first degree; 
Cardiac disorders - Other (bundle branch block left); Cardiac disorders - Other (extrasystoles); Chest pain 
- cardiac; Heart failure; Myocardial infarction; Palpitations; Pericardial effusion; Pericarditis; Sinus 

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48 
bradycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear pain  
EYE DISORDERS - Conjunctivitis; Dry eye; Eye disorders - Other (eye discharge); Eye disorders - Other 
(macular edema); Eye disorders - Other (ocular hyperemia); Eye disorders - Other (retinal hemorrhage); 
Eye disorders - Other (visual acuity reduced); Eye pain; Floaters; Glaucoma; Keratitis; Photophobia; 
Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Cheilitis; Colitis; Dyspepsia; Enterocolitis; 
Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(gluteal intramuscular bleed); Gastrointestinal disorders - Other (irritable bowel syndrome); 
Gastrointestinal disorders - Other (tongue discoloration); Oral dysesthesia; Oral pain; Pancreatitis; 
Periodontal disease; Small intestinal obstruction; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Flu like symptoms; Gait 
disturbance; General disorders and administration site conditions - Other (early satiety); General 
disorders and administration site conditions - Other (multiple organ dysfunction syndrome); General 
disorders and administration site conditions - Other (sensation of foreign body); General disorders and 
administration site conditions - Other (temperature intolerence); Infusion related reaction; Injection site 
reaction; Localized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and procedural 
complications - Other (excoriation) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT corrected interval 
prolonged; INR increased; Investigations - Other (cardiac murmur); Investigations - Other (increase CRP); 
Lymphocyte count decreased; Weight gain; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hypoalbuminemia; 
Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (cachexia); Metabolism and nutrition disorders - Other (fluid 
retention); Metabolism and nutrition disorders - Other (hyperphosphatemia); Metabolism and nutrition 
disorders - Other (hypoproteinemia); Metabolism and nutrition disorders - Other (lactose intolerence) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; 
Flank pain; Generalized muscle weakness; Joint effusion; Joint range of motion decreased; 
Musculoskeletal and connective tissue disorder - Other (groin pain); Musculoskeletal and connective 
tissue disorder - Other (muscle rigidity); Musculoskeletal and connective tissue disorder - Other (pain in 
jaw); Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Dysgeusia; Encephalopathy; 
Leukoencephalopathy; Memory impairment; Nervous system disorders - Other (mental impairment); 
Nervous system disorders - Other (parosmia); Nervous system disorders - Other (PML); Paresthesia; 
Reversible posterior leukoencephalopathy syndrome; Sinus pain; Somnolence; Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Insomnia; Restlessness 
RENAL AND URINARY DISORDERS - Cystitis noninfective; Renal and urinary disorders - Other 
(calculus bladder); Renal and urinary disorders - Other (polyuria); Urinary frequency; Urinary retention; 
Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dyspareunia; Reproductive system and breast 
disorders - Other (hematospermia); Vaginal dryness 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Hiccups; Laryngeal 
inflammation; Pleural effusion; Pneumonitis; Productive cough; Respiratory failure; Respiratory, thoracic 
and mediastinal disorders - Other (alveolitis allergic); Respiratory, thoracic and mediastinal disorders - 
Other (nasal ulcer); Sinus disorder; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Nail discoloration; Nail loss; 
Periorbital edema; Photosensitivity; Pruritus; Skin atrophy; Skin hyperpigmentation; Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Flushing; Hot flashes; Thromboembolic event; Vascular disorders - Other 
(peripheral coldness) 

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49 
 
Note: Ibrutinib (PCI-32765) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
7.1.2 Serious Adverse Event Reported in 9922 
 
CYTOKINE RELEASE SYNDROME – Dehydration, hypotension potentially requiring 
pressors, fever without infection 
 
7.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting beginning April 1, 2018.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the grade 
is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in Section  
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event  
Reporting System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  
The reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 

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50 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “ General disorders and administration site conditions.  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Note:  Adverse events that occur from the date of signed informed consent through 30 
days after administration of the last dose of study drug, whether or not related to study 
drug(s), that meets criteria for expedited reporting must be submitted to CTEP-AERS. 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death. 
2) 
A life-threatening adverse event. 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours. 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 

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51 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Events of Special Interest 
 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the Sponsor.  These events will be reported to the Sponsor via CTEP-
AERS within 24 hours of awareness following the procedure described above for SAEs and will 
require enhanced data collection.  All Events of Special Interest will be submitted within 24 
hours of awareness even if they do not meet serious criteria. 
 
• Major Hemorrhage 
Major hemorrhage is defined as any hemorrhagic event that is grade 3 or greater in severity, 
or that results in one of the following: intraocular bleeding causing loss of vision, the need 
for a transfusion of two or more units of red cells or an equivalent amount of whole blood, 
hospitalization, or prolongation of hospitalization.  Events meeting the definition of major 
hemorrhage will be captured as an event of special interest as described above. 
 
• Intracranial Hemorrhage 
Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, 
epidural hematoma/hemorrhage, and intracerebral hemorrhage, of any grade severity, will be 
captured as an event of special interest, as described above. 
 

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52 
• Pregnancy 
All initial reports of pregnancy must be reported to the Sponsor by the study site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form.  Abnormal pregnancy outcomes (e.g., spontaneous abortion, stillbirth, and congenital 
anomaly) are considered SAEs and must be reported in a timely fashion.  Any subject who 
becomes pregnant during the study must discontinue further study treatment. 
 
7.4 Routine Adverse Event Reporting 
 
7.4.1 Definitions 
 
Adverse Event  
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal laboratory 
finding, symptom, or disease temporally associated with the use of a drug) in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) need not be considered AEs and should not be recorded as 
an AE.  Disease progression should not be recorded as an AE, unless it is attributable by the 
investigator to the study therapy. 
 
Suspected Adverse Reaction 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the 
drug is the cause.   Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration of the 
following factors: temporal relationship of the AE to study drug exposure, known mechanism of 
action or side effect profile of study treatment, other recent or concomitant drug exposures, 
normal clinical course of the disease under investigation, and any other underlying or concurrent 
medical conditions.  Other factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon rupture); often 
more than once occurrence from one or multiple studies would be needed before 
the sponsor could determine that there is reasonable possibility that the drug 
caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that indicates 
the events occur more frequently in the drug treatment group than in a concurrent 
or historical control group 

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53 
 
Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not consistent with 
the applicable product information (e.g., Investigator’s Brochure (IB) for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product).  Unexpected also refers to AEs or SARs that are mentioned in the IB as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
 
Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or sponsor, 
it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from the 
event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of existing 
hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  For reporting purposes, also 
consider the occurrences of pregnancy as an event which must be reported as 
an important medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as administration 
of chemotherapy, central line insertion, metastasis interventional therapy, resection of 
primary tumor, or elective surgery, will not be considered serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
 
7.4.2 Reporting of Adverse Events 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 

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7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  This includes all new malignant tumors, including solid 
tumors, skin malignancies and hematologic malignancies.  Such malignancies are to be reported 
for the duration of study treatment and during any protocol-specified follow-up periods, 
including post-progression follow-up for overall survival.  Second malignancies require ONLY 
routine AE reporting unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 CTEP-supplied Agent 
 
8.1.1 Ibrutinib (NSC #748645) 
 
Chemical Name:  1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-
1-piperidinyl]-2-propen-1-one 
 
Other Names: 
Imbruvica, PCI-32765 
 
Classification: Selective, irreversible, small molecule inhibitor of Bruton’s tyrosine kinase 
(Btk). 
 
CAS Registry Number:  936563-96-1 
 
 
 
M.W.:  440.5 g/mole 

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Mode of Action:  Ibrutinib binds covalently to a cysteine residue in the Btk active site, leading 
to potent and irreversible inhibition of Btk enzymatic activity of BCR.  B-cell maturation is 
mediated by BCR signal transduction and Btk is an essential part of the signaling pathway. 
 
Description: White to off-white crystalline solid 
 
How Supplied:  Ibrutinib is supplied by Pharmacyclics, Inc., and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Ibrutinib is supplied as hard gelatin 
capsules containing micronized ibrutinib and the following excipients:  microcrystalline 
cellulose; croscarmellose sodium; sodium lauryl sulfate; may contain magnesium stearate.  
Capsules are manufactured as 140mg in a size 0, gray, hard gelatin capsule.  Capsules are 
packaged in high-density polyethylene (HDPE) bottles with an induction seal and a child-
resistant screw top cap.  Each bottle contains 92 capsules.  Ibrutinib capsules are to be dispensed 
in their original containers. 
 
Storage:  Ibrutinib Hard Gelatin Capsules should be stored at 15°C to 25°C (59°F to 77°F) with 
excursions permitted to 30°C (86°F). 
 
Stability:  Shelf life surveillance of the intact bottles is ongoing. 
 
Route of Administration:  Orally, with 8 ounces (approximately 240ml) of water.  The capsules 
are to be swallowed intact.  Ibrutinib must not be taken with grapefruit juice. Doses are to be 
taken at about the same time each day.  If a dose is missed, it should be taken as soon as possible 
on the same day with a return to the normal schedule the following day.  Patients should not take 
extra capsules to make up the missed dose. 
 
Potential Interactions:  Ibrutinib is primarily metabolized by CYP3A4.  Any strong inhibitor or 
inducer of CYP3A4 (e.g., itraconazole, ketoconazole, clarithromycin, and rifampin) should be 
administered with caution and only after consultation with the Medical Monitor.  Grapefruit and 
Seville orange juices should be avoided. 
 
Availability 
 
Ibrutinib is an investigational agent supplied by Pharmacyclics and distributed to investigators 
by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Ibrutinib is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 

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8.1.2.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission 
of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator 
Data Form (IDF), and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should be 
ordered under the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an ‘active’ account status 
and a ‘current’ password.  For questions about drug orders, transfers, returns, or 
accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Oral Drug Accountability Record Form (DARF).  (See 
the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 Integral Laboratory or Imaging Studies 
 
N/A 
 
9.2 Investigational Device Information 
 
N/A 
9.3 Integrated/Exploratory Correlative Studies 
 
9.3.1 Archived/Fresh Tumor Tissue - Expression of the Integrated Biomarker ITK and/or  
Other Exploratory Putative Targets of Ibrutinib in Melanoma 
 
We hypothesize that the overall response rate (ORR) and/or PFS after ibrutinib initiation will be 
associated with increased expression of ITK protein by melanoma cells. As shown in Table 2 
(see Section 2.3.4), ibrutinib has several high-affinity targets in addition to ITK and BTK; 
several of these targets have been previously shown to play a role in melanoma biology (e.g. 
HER2, HER4, Csk, EGFR, YES, cFGR, ErbB4, Tec, Hck, BTK). Therefore, we cannot exclude 

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that the protein expression of other putative targets by melanoma cells could also be predictive of 
clinical benefit to ibrutinib, either independent from or in combination with ITK. We will 
prioritize evaluation of ITK, because it is the only integrated biomarker for this study. The other 
targets (e.g. HER2, HER4, Csk, EGFR, YES, cFGR, ErbB4, Tec, Hck, BTK) are exploratory 
markers and will be evaluated if adequate tissue is available for assessment of these proteins.  
 
The protein expression levels of various putative targets of ibrutinib that also have a known 
biological role in melanoma will be assessed by IF and will be analyzed with Aperio imaging 
(Schlegel et al., 2013; Nikolaishvilli-Feinberg et al., 2014; Carson et al., 2015). More 
specifically, up to fifteen 5-micron tissue section will be prepared on positively charged slides 
from corresponding archived or fresh FFPE tumor blocks. Given that abundance of tumor tissue 
may be variable for such studies the following stains will be performed with a decreasing order 
of importance: 
 
• standard hematoxylin and eosin stain to assess percent of viable tumor, tumor/stroma 
ratio, and immunoscore analysis (quality control). Total of one slide. 
 
• 2-color IF using antibodies against ITK and each of the ‘primary’ ibrutinib targets (ITK, 
EGFR, ERBB4, YES, cFGR). This method will allow differentiation between their 
expression in melanoma cells (S100+; third stain) versus stromal cells (S100-). Total of 
five slides with the following decreasing order of importance 
(ITK>EGFR>ERBB4>YES>cFGR). 
 
• 2-color IF using antibodies against the ‘secondary’ ibrutinib targets (TXK, BMX, TEC, 
BTK, and HCK). Total of five slides with the following decreasing order of importance 
(BTK>HCK>TEC>BMX>TXK). 
 
Image analysis involves definition of electronic gates for tumor using an electronic pen tool. 
Then the S100-positive regions of interest (ROI) will be defined by Definiens Tissue Studio 
technology (Definiens Architect v.2.5.0 Build 44725 x64, Tissue Studio Library v4.2).Using 
the "Cell membrane nuclei" composer algorithm of the Definiens Architect XD we will 
calculate ITK expression in S100+ regions of interest (ROI; melanoma cells). The 
significance of protein expression measured by H-score (continuous variable) as a predictor 
of antitumor response and PFS will be explored.  
 
9.3.1.1 Archived Tumor Tissue - Collection of Specimen(s) 
 
Blocks/slides from pre-treatment, FFPE archived tumor tissue from diagnosis of metastatic 
disease will be collected. Based on our published data, ITK expression is significantly higher 
in metastatic melanomas, irrespective of stage (regional stage III, or distant metastatic stage 
IV) compared to primary; therefore, eligible archived tumor blocks can also be from positive 
sentinel lymph node mapping procedures or regional lymphadenectomies. Consent to allow 
access to archival tissue is required for enrollment.  Once consent is signed, research 
personnel should begin the process of accessing archival tissue and determining if tissue has 
sufficient tumor to support tumor imaging studies. 
 

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Confirmation of sufficient tumor should be obtained from the participating institution 
pathologist. However, in situations where obtaining confirmation from the participating 
institution pathologist may cause significant delay in starting the patient on study treatment, 
the Lead Principal Investigator may be able to review pathology information to determine 
eligibility.  Below are details for each process. 
 
Pathologist from Participating Site 
A pathologist from each participating academic institution (or local pathologist if applicable) 
may review tumor blocks to ensure sufficient tumor is available for support of correlative 
studies for this protocol. An institution pathologist is required to sign-off (see Appendix B 
for sample letter) regarding the:  
 
a) availability of metastatic FFPE blocks,  
 
b) quality of tumor tissue based on review of H&E stained section; tumor tissues with 
at least 70% viable tumor are suitable for analysis, and  
 
c) sufficient amount of tumor tissue for tumor imaging analysis (IF).  
 
If metastatic tumor samples are available and of sufficient quantity and quality, metastatic 
tumors will be used for analysis because we have previously shown that expression of ITK is 
higher is metastatic melanoma as opposed to primary melanoma (Carson et al., 2015).  
 
The signed pathologist letter should be uploaded with the rest of the eligibility documents to 
the 9922 Study Portal by accessing: http://j.mp/2eup4yF. Additional information about the 
study portal use is available in LPO Documents for the study on www.ctsu.org. 
 
Lead Principal Investigator 
The processes involved for a participating institution pathologist to sign off on archival 
tumor tissues may be time-consuming and could delay enrollment. Therefore, to minimize 
delay, in lieu of the institutional pathologist, the Lead Principal Investigator may confirm 
eligibility of subject’s archival tissue based on information provided from participating sites.  
Confirmation by the Lead Principal Investigator requires the participating site to submit the 
following materials (de-identified and labeled with subject screening ID number and 
initials) to the Lead Protocol Organization: 
 
• pathology report(s) and stained slides (e.g., hematoxylin-eosin, and/or S100, melin-
A/MART-1, tyrosinase, or MITF) shipped directly to address provided below. 
 
-OR-  
 
• pathology report(s) and corresponding digital images emailed directly to Study 
Coordinators as instructed below. 
 
Study Coordinators will facilitate the pathology review by the Lead Principal Investigator.  
Requests for the Lead Principal Investigator’s review of pathology for determination of 

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subject eligibility must be emailed with a copy of the subject’s pathology report (de-
identified and labeled with subject screening ID number and initials) attached to the 
email. The information should be provided to the following: 
 
Kimberly_Keller@med.unc.edu 
 
The stained slides with associated pathology reports should be sent via priority courier 
delivery (eg. FedEx) to the Lead Principal Investigator’s address as follows:   
 
Dr. Stergios Moschos, 9922 Lead PI 
University of North Carolina at Chapel Hill 
Physician’s Office Building, Suite 3116-CB#7305 
Chapel Hill, NC 27599 
Telephone: 919-843-7713 
 
The Lead Principal Investigator will review subject pathology materials and if confident 
there is sufficient archival tissue available for study enrollment, confirmation will be 
provided to the participating site by the Study Coordinator. Refer to Appendix B for 
documentation that will be provided by the Lead Principal Investigator in lieu of the site 
pathologist in this case.  If determination of sufficient archival tissue cannot be made by the 
Lead Principal Investigator based on the information provided, this will be noted. In this 
case, responsibility for confirming that adequate tissue is available is transferred back to the 
site pathologist for confirmation of eligibility. 
 
9.3.1.2 Fresh Biopsy of Metastatic Tissue – Collection of Specimens 
 
If patients do not have available archival tumor tissue from metastatic melanoma OR the 
pathologist or Lead Principal Investigator cannot assure that “sufficient” amount of good 
quality is available from an existing archived tumor tissue from metastatic melanoma, then 
patients must consent to undergo a tumor biopsy from a metastatic site. If palpable tumors 
from a metastatic site are available, then excisional or core biopsies can be performed. If, 
however, palpable tumors are not available then a core biopsy procedure using an 18-gauge 
needle will be performed by interventional radiology. Only intra-abdominal lesions will be 
subjected to core biopsy because intra-thoracic procedures have a significantly higher 
frequency of complications. In other words, if a patient does not have sufficient metastatic 
tissue available from archival tumor tissue and has lung lesions as the only site of metastatic 
disease, then the patient is not eligible for this trial. The number of cores obtained will be 
affected by the patient’s clinical condition at the time of biopsy and is determined by the 
health care professional, who is performing the procedure. Therefore, it is possible that more 
than one core (up to 5) may be procured for this research project but ultimately, the amount 
of tissue available for correlative studies can be variable. A rapid on-site evaluation (cytology 
with quick hematoxylin and eosin stains) should be available in each institution to evaluate 
the quality of tumor sample (i.e. percent of tumor cells and amount of necrosis). 
 
Fresh biopsy cores will be subject to:  
 

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• Immediate and overnight fixation in 10% buffered formalin for paraffin-embedding, 
usually within 20-24 hours after fixation. For biopsies performed on Friday, fixation 
time may extend to 48 hours (FFPE samples). 
 
• The FFPE samples must also provide a histological confirmation for the presence and 
cellularity of melanoma cells as well as amount of necrosis. 
 
Quality Control (QC): All tissue specimens collected will be reviewed by a board-certified 
pathologist. QC activities for specimens collected include a) histology/cytology examination 
of the tissues and cells; b) tissue quality assessment of fresh specimens to prepare histology 
specimens such as whole sections for 2-color IF. All histology stained samples will be 
scanned and digital images will be available for review. 
 
Histology: H&E-stained sections from core needle biopsies will be used to confirm the 
presence of tumor cells, as well as their abundance (tumor cellularity), stromal components 
and lymphocytic infiltrates. H&E-stained sections from all FFPE diagnostic slides will be 
scanned into Aperio™ digital pathology scanner analysis for pathological evaluation and 
selection for biomarker analysis.  
 
Distribution: the percent of the section that includes a mononuclear infiltrate. Takes into 
account whether infiltrate is focal, multifocal or diffuse. 0, 1+, 2+, 3+ if 0, 1-25%, 26-50%, 
and ≥50% of the tumor section, respectively. 
 
Density: the average density of the mononuclear infiltrate in areas where a lymphoid 
infiltrate is present. 0, 1+, 2+, 3+ if absent, mild, moderate, severe, respectively. 
 
Note:  Patients with insufficient (archival or fresh) tissue will NOT be eligible for this 
study. CTEP will provide remuneration for the fresh biopsy collection. 
 
Tumor Block Preparation: 
• Labeled each block with: 
- 
Study Number NCI9922 
- 
Subject ID Number  
- 
Date of Specimen 
- 
Block Accession Number  
• Complete one NCI9922 Archival Tissue Block/Slides Submission Form (see 
Appendix E for submission form) per patient. 
• Submit the corresponding pathology report(s).  Remove name, MRN or any other PHI 
from the pathology report.  Write the study number NCI9922, subject’s initials and 
subject’s ID number on the pathology report. 
 
Tumor Slide Preparation:  
• Use positively charged microscope slides, such as Superfrost Plus Fisher Catalog 
#22-034-979 or #12-550-15. 
• Cut a minimum of 11 unstained slides to a maximum of 15 unstained slides.   
• Section thickness should be 5 microns.  

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• Stain one additional slide for H&E; the 11-15 slides are unstained.   
• Slide drying should be performed at 37°C overnight.  
• Storage of cut slides at room temperature should ideally not exceed more than 7 days.  
• Longer-term storage should be at 4°C, with slide boxes carefully parafilmed to 
prevent moisture entering the slide box or alternatively, tissue can be stored in a 
dessicator or a nitrogen chamber.  
• Mark each slide with: 
- 
Study Number NCI9922 
- 
Subject ID Number  
- 
Date of Specimen 
- 
Block Accession Number  
- 
Serial Number of Slide (1, 2, 3…) 
• Complete one NCI9922 Archival Tissue Block/Slides Submission Form (see 
Appendix E for submission form) per patient. 
• Submit the corresponding pathology report(s).  Remove name, MRN or any other PHI 
from the pathology report.  Write the study number NCI9922, subject’s initials and 
subject’s ID number on the pathology report. 
 
9.3.1.3 Archived/Fresh Tumor Tissue - Handling of Specimens(s) 
 
Each participating institution will collect archived or fresh specimens and ship them to 
the UNC Tissue Procurement Facility within 8 weeks after the start of study treatment for 
each subject. FFPE blocks (or representative tissue sections from FFPE blocks) will be 
handled following standard operating procedures for biohazardous materials (i.e., tumor 
blocks placed on individual biohazardous bags whereas glass slides placed of slide 
holders).  
 
9.3.1.4 Archived/Fresh Tumor Tissue - Shipping of Specimen(s) 
 
Specimens collected for correlative analysis of FFPE blocks or representative 5-micron 
tumor tissue sections (i.e., slides) must be shipped within 8 weeks after each patient starts 
study treatment to the UNC-CH Tissue Procurement Facility (TPF) for analysis in the 
end of the trial. This means that upon study enrollment of each patient, shipping of tumor 
tissue is NOT required; only the sign-off letter by the institutional pathologist (or Lead 
Principal Investigator) is sufficient to enroll the patients. 
 
Archival tissue specimens along with corresponding de-identified pathology reports and 
completed NCI9922 Archival Tissue Block/Slides Submission Form must be shipped 
within 8 weeks after each subject starts study treatment by courier (Monday-Thursday) 
guaranteeing overnight delivery to the following address:    
 
Mei Huang, Lab Manager      
c/o Tissue Procurement Facility 
108 MacNider Building, CB 7304 
University of North Carolina 
333 South Columbia St 

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Chapel Hill, NC 27599 
Phone: 919-966-2620 
Unc_tpf@med.unc.edu 
 
Note:  If shipping in hot weather, include a refrigerated gel pack with the slides.  Do 
NOT ship on dry ice or wrap the slides in gauze.   
 
Please notify the UNC Tissue Procurement Facility (unc_tpf@med.unc.edu) of incoming 
shipment by providing notification on the day of shipment via the 9922 Study Portal.  
The shipment notification will include upload of the associated Archival Tissue 
Block/Slides Submission Form (see Appendix E). Additional information about study 
portal use is available in LPO Documents for the study on www.ctsu.org.   
 
9.3.1.5 Site(s) Performing Correlative Study 
 
Tumor imaging studies (2-color IF) will be performed at the UNC-CH Translational 
Pathology Laboratory (https://tpl.med.unc.edu). 
 
9.4 Exploratory/Ancillary Correlative Studies 
 
See Sections 2.3 and 2.4 for background information on correlative studies. 
 
9.4.1 Peripheral Blood Mononuclear Cell (PBMC) - Effect of Ibrutinib on Immune  
Regulatory Cell Populations 
 
We hypothesize that ibrutinib does not have any inhibitory effect upon host immune response, 
but may have beneficial effects by reversing melanoma-mediated Th2-bias, which does not lead 
to effective antitumor response (Tatsumi et al., 2002). 
 
PBMC from three different time points (pre-study, pre-dose on Day 1 of Cycle 2, and at disease 
progression) will be stained for various immune regulatory cell populations, as well as markers 
for Th1 and Th2 responses to investigate the effect of ibrutinib on host immune response, in 
particular the reversal of Th2-to-Th1 bias, as previously described (Dubovsky et al., 2013). 
Specifically, the following immune cell subsets will be assayed using multi-parameter flow 
cytometry: 
 
ITK expressing T cell subsets 
T-helper: 
 
 
 
            CD3+CD8—CD4+ITK± 
T-cytotoxic: 
 
 
                        CD3+CD4—CD8+ITK± 
Invariant natural killer T cells (iNKT):  
Vα24+Vβ+CD3+ITK± 
Gamma delta γδT cells:  
 
            CD3brightgdTCR+CD16+CD57+ 
 
T-helper cell subtypes 
Pro-inflammatory (Th1): 
 
            CD3+CD4+IFNγ+ (or T-bet+) 
Anti-inflammatory (Th2):  
 
            CD3+CD4+IFNγ+ (or GATA3+) 
Th9: 
 
 
 
                        CD3+CD4+IL9+ 

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Th17:  
 
 
                        CD3+CD4+IL17A+ 
 
Immunoregulatory populations 
Naturally occurring T regulatory cells:  
            CD4+CD25high+FoxP3+ 
Type I regulatory T cells: 
 
                        CD4+CD25+(IL10 or TGFβ)+,  
Myeloid-derived suppressor cells, monocytic type:   HLA-DRlow+CD14+;  
Myeloid-derived suppressor cells, other,                    lin1—HLA-DR—CD33+CD11b+ 
Myeloid-derived suppressor cells, lymphoid type:     lin1—/HLA-DR—/CD33+/CD11b+ 
 
Within-patient changes in the expression of particular immune cell subsets from pre-study (i.e., 
baseline) to pre-dose on Day 1 of Cycle 2 (i.e., Day 29) and at disease progression will be 
assessed and used to develop a profile of immune response in peripheral blood that distinguishes 
patients who respond to treatment versus those who do not.  
 
A total of 50 mL of blood will be collected for flow cytometric analysis for each time point. This 
amount of blood is justified by the fact that: (a) patients with metastatic melanoma are usually 
lymphopenic, (b) certain immune cell subsets are rare (<1% of immune cell subsets) events [e.g. 
myeloid-derived suppressor cells, invariant natural killer T cells (iNKT), γδT cells], and 
therefore sufficient peripheral blood is required to detect those rare populations.   
 
9.4.1.1 PBMC - Collection of Specimen(s) 
 
Collection and Processing: 
• Collect peripheral blood in five 10mL green-top (sodium heparin) tubes (BD 
Vacutainer, Catalog no. 366480) at the following time points (on Monday, Tuesday, 
and Wednesday only):   
a) pre-study (i.e., baseline); 
b) pre-dose on Day 1 of Cycle 2 (i.e., Day 29); and  
c) disease progression. 
• Label each sample with:    
- 
Study Number NCI9922 
- 
Sample Type PBMC 
- 
Subject ID Number  
- 
Collection Date 
- 
Collection Time 
 
9.4.1.2 PBMC - Handling of Specimens(s) 
 
Plasma extractions and Ficoll-enriched PBMC isolation will be performed per UNC 
institutional standard procedures in the UNC Biospecimen Facility (BSP) on the same 
day samples arrive. Whole blood samples will be separated into plasma and PBMCs as 
described below. Blood tubes will be spun at 400 x g for 10 minutes, after which plasma 
will be removed and aliquoted as follows. Two mls of the plasma will be used to prepare 
twenty 100ul aliquots. The remainder of the plasma will be aliquoted into 1ml aliquots up 
to a total of 18. Plasma aliquots will be stored at -80°C. After plasma extraction the rest 
of the whole blood will be diluted with calcium and magnesium free PBS and PBMCs 

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will be isolated by centrifugation over Ficoll-Paque Plus. After isolation PBMCs will be 
counted and cryopreserved in as many 5 x 106 aliquots as possible. PBMCs will be stored 
at -80°C overnight before transfer to long-term storage into vapor-phase LN2 storage. 
 
9.4.1.3 PBMC - Shipping of Specimen(s) 
 
Whole green-top blood tubes will be shipped on Monday, Tuesday, and Wednesday 
only at ambient temperature via priority overnight delivery to the following address:    
 
ATTN: Patricia Basta, PhD 
Biospecimen Processing Facility 
135 Dauer Dr. 
Michael Hooker Research Center Room 3213 
University of North Carolina – Chapel Hill, Chapel Hill 27599 
Phone: 919-966-7738 
 
Please notify the UNC Biospecimen Facility (patricia_basta@unc.edu) of any incoming 
shipment by providing notification two days prior to shipment via the 9922 Study Portal. 
The shipment notification will include upload of the associated PBMC Shipment Log 
(see Appendix G). Additional information about study portal use is available in LPO 
Documents for the study on www.ctsu.org.   
 
9.4.1.4 PBMC - Site(s) Performing Correlative Studies 
 
Analysis will be performed at the UNC-CH Flow Cytometry Core Laboratory. 
 
9.4.2 Plasma - Protein Markers Associated with Sensitivity or Resistance to Ibrutinib  
 
Multiplex ELISA assays have been developed to analyze over 25 angiogenic, inflammatory and 
immune-related markers in less than 0.5 ml of plasma.  Coefficients of variation for most 
analytes are <10%.  This platform has been successfully applied to several in-house phase I and 
II studies, as well as several phase III, Alliance-conducted studies with bevacizumab in 
colorectal and other cancers at Duke University. Markers of inflammation will be analyzed in the 
Duke Phase I Biomarker Lab, which serves as a core lab for these analyses for the US 
Cooperative Group, the Alliance.  
 
Analyses will be performed on pre-treatment and on-treatment plasma samples and on samples at 
disease progression. Analyte levels, and changes in analyte levels, will be correlated with clinical 
outcome (ORR, PFS, and OS).  Plasma will also be evaluated for protein markers that may be 
associated with sensitivity or resistance to ibrutinib. These may include CRP and other markers 
of inflammation, including but not limited to IFNγ, IL1β, IL6, sILR6R, sGP130, IL4, IL7, IL10, 
IL12, IL17A, IL17E, and IL23. Additional markers of proteins regulated by the PD-1/PD-L1 
interaction and the IL6/JAK-STAT axis will also be assessed, including but not limited to VEGF, 
HER and TGFβ family members. 
 

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9.4.2.1 Plasma - Collection of Specimen(s) 
 
Collection and Processing: 
• Draw one 10ml lavender top (K2EDTA) tube (BD Vacutainer, Catalog no. 366643) at 
the following time points: 
a) pre-study (i.e., baseline); 
b) pre-dose on Day 1 of Cycle 2 (i.e., Day 29);   
c) pre-dose Day 1 on each odd numbered cycle (i.e., at each restaging at Cycles 
3, 5, etc.) 
d) disease progression. 
• Invert tubes 10 times to mix blood. 
• Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions). 
• Remove plasma from the tube and transfer equally into two separate clean 15ml 
polypropylene tubes (or institutional equivalent). 
• Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions). 
• Aliquot approximately 1.0 ml of plasma per cryovial (i.e., 1 ml of plasma per cryovial 
into four 2.0 ml cryovials).  
• Snap freeze (put into liquid nitrogen) or place into -800C freezer as soon as possible 
after collection 
• Label each cryovial with:    
- 
Study Number NCI9922 
- 
Sample Type Plasma 
- 
Subject ID Number  
- 
Collection Date 
- 
Collection Time 
- 
Frozen Time 
 
9.4.2.2 Plasma - Handling of Specimens(s) 
 
Plasma samples will be stored at -80°C until further use.  
 
9.4.2.3 Plasma - Shipping of Specimen(s) 
 
In the end of trial accrual, all protein marker (plasma) and pharmacogenomics (whole 
blood) specimens will be batched (approximately 2 batches per institution) and shipped 
on dry ice by courier guaranteeing overnight delivery (Monday-Thursday) to the 
following address:    
 
Phase I Biomarker Laboratory 
ATTN: Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
66 
Phone: 919- 681-2239 
 
Please notify the Phase I Biomarker Laboratory (jchris.brady@duke.edu) of any 
incoming shipment by providing notification on the day of shipment via the 9922 Study 
Portal.  The shipment notification will include upload of the associated Biomarker 
Shipment Log (see Appendix H). Additional information about study portal use is 
available in LPO Documents for the study on www.ctsu.org.   
 
Directions for how to prepare and ship samples on dry ice are available at:  
http://www.iata.org/whatwedo/cargo/dangerous_goods/Documents/DGR52_PI650_EN.p
df 
 
9.4.2.4 Plasma - Site(s) Performing Correlative Studies 
 
Protein marker analysis will be performed at the Duke Phase I Biomarker Laboratory. 
 
9.4.3 Whole Blood - Pharmacogenomics Assessment 
 
A one-time, blood sample will be drawn prior to initiation of therapy for assessment of variants 
in genes anticipated to be involved in the pharmacokinetics or pharmacodynamics of ibrutinib.  
 
9.4.3.1 Whole Blood - Collection of Specimen(s) 
 
Collection and Processing: 
• Draw one 6ml pink top (K2EDTA) tube (BD Vacutainer, Catalog no. 367899) or a 
purple-top (K2EDTA) tube (BD Vacutainer, Catalog no. 367863) at the following 
time point: 
a) prestudy (i.e., baseline) only. 
• Invert tube 10 times to mix blood. 
• Freeze tube in an upright position as soon as possible at -200C for 24 hours, and then 
transfer to -800C for long term storage 
• Label the tube with:    
- 
Study Number NCI9922 
- 
Sample Type Whole Blood 
- 
Subject ID Number  
- 
Collection Date 
- 
Collection Time 
- 
Frozen Time 
 
9.4.3.2 Whole Blood - Handling of Specimens(s) 
 
Whole blood samples will be stored at -80°C until further use.  
 
9.4.3.3 Whole Blood - Shipping of Specimen(s) 
 
In the end of trial accrual, all protein marker (plasma) and pharmacogenomics (whole 

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67 
blood) specimens will be batched (approximately 2 batches per institution) and shipped 
on dry ice by courier guaranteeing overnight delivery (Monday-Thursday) to the 
following address:    
 
Phase I Biomarker Laboratory 
ATTN: Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
Phone: 919-681-2239 
 
Please notify the Phase I Biomarker Laboratory (jchris.brady@duke.edu) of any 
incoming shipment by providing notification on the day of shipment via the 9922 Study 
Portal.  The shipment notification will include upload of the associated Biomarker 
Shipment Log (see Appendix H). Additional information about study portal use is 
available in LPO Documents for the study on www.ctsu.org.   
 
Directions for how to prepare and ship samples on dry ice are available at:  
http://www.iata.org/whatwedo/cargo/dangerous_goods/Documents/DGR52_PI650_EN.p
df 
 
9.4.3.4 Whole Blood - Site(s) Performing Correlative Studies 
 
Pharmacogenomic analysis will be performed at the Duke Phase I Biomarker Laboratory. 
 
9.5 Special Studies 
 
9.5.1 Pharmacokinetic (PK) Study 
 
Plasma concentrations of ibrutinib and metabolite PCI-45227 after repeated dosing will be 
determined using a validated analytical method.  Refer to Section 10 of Study Calendar for PK 
collection time points (see footnote #17).   
 
9.5.1.1 PK – Collection of Specimen(s) 
 
Collection and Processing: 
1. Draw one 2ml GREEN TOP PLASTIC SODIUM HEPARIN TUBE (Greiner Bio-
One via Fisher Scientific, Catalog no. 454302) for each PK collection at the following 
time points: 
- 
pre-dose on Day 1 of Cycle 1 
- 
pre-dose on Day 8 of Cycle 1 
- 
post-dose on Day 8 of Cycle 1 at 
• 0.5 hour 
• 1 hour 
• 2 hours 
• 4 hours 

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68 
• 6 hours 
• 24 hours 
2. Allow tube to fill COMPLETELY, as far as the vacuum will allow. 
3. Mix the tube immediately upon completion to avoid clotting by inverting gently 5 
times. DO NOT SHAKE. 
NOTE: Sample should be processed and stored within 1 hour of collection. 
4. Place the tube on melting ice until centrifugation. 
5. Place the tube in a refrigerated centrifuge (0-4°C). 
NOTE:  Use a refrigerated centrifuge bucket in cases where a refrigerated 
centrifuge is not available.  Maintain cold temperature during the plasma 
preparation process. 
6. Centrifuge the tube within 60 minutes of collection at 4°C for 15 minutes at 2500 
rpm. 
7. Transfer plasma with pipette equally into two 2mL cryovials (approximately 0.5 mL 
of plasma in each tube). 
8. Label each cryovial with: 
- 
Study Number NCI9922 
- 
Sample Type PK 
- 
Subject ID Number 
- 
Collection Date 
- 
Collection Time 
- 
Frozen Time 
 
9.5.1.2 PK – Handling of Specimen(s) 
 
Store plasma samples in a freezer at -70°C or below, within approximately 60 minutes of  
blood collection. 
 
NOTE:  Every effort should be made to collect the full 2mL blood sample at each 
time point.  In the event that less than 1mL of blood is collected, the sample will be 
processed as described above except that the plasma will not be divided into two 
cryovials. All deviations will be recorded on the PK Shipment Log provided in 
Appendix I. This single plasma sample should be frozen, stored and shipped with 
the primary set of samples. 
 
9.5.1.3 PK – Shipping of Specimen(s) 
 
Each subject’s primary samples from Cycle 1 Day 1 and Cycle 1 Day 8 should be 
shipped together.  Make sure to separate primary and back-up samples. Do NOT ship 
back-up aliquots of plasma in the same shipment as the primary samples from the same 
subject. Back-up samples should be held until authorized to ship.  
 

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69 
On a quarterly basis, PK specimens will be batch shipped on Monday, Tuesday, and 
Wednesday only FROZEN on dry ice via priority overnight delivery to the following 
address:   
 
Mei Huang, Lab Manager 
c/o Tissue Procurement Facility 
108 MacNider Building, CB 7304 
University of North Carolina 
333 South Columbia St 
Chapel Hill, NC 27599 
Phone: 919-966-2620 / Fax: 919-843-9501  
 
Contact delivery (ex. FedEx) customer service to determine the latest pickup time for 
your site and the scheduling deadline. Allow ample time for delivery.  Shipments cannot 
be received on Friday afternoons, weekends, days preceding holidays, or holidays.  Any 
questions regarding holiday schedules may be addressed to contact person below.   
 
Mei Huang, Lab Manager 
Phone: 919-966-2620  
Email: mei_huang@med.unc.edu 
 
For each shipment include the completed NCI 9922 Pharmacokinetics Sample 
Submission Form (see Appendix I) on the outside of the Styrofoam box for each 
patient’s samples contained in the shipment.  If shipping samples for different subjects in 
the same shipping container, make sure they are labeled properly and placed in separate 
bags or boxes. 
 
Please notify the UNC Tissue Procurement Facility (unc_tpf@med.unc.edu) of any 
incoming shipment by providing notification on the day of shipment via the 9922 Study 
Portal.  The shipment notification will include the upload of the associated 
Pharmacokinetics Sample Submission Form (see Appendix I). Additional information 
about study portal use is available in LPO Documents for the study on www.ctsu.org.   
 
Directions for how to prepare and ship samples on dry ice are available at:  
http://www.iata.org/whatwedo/cargo/dangerous_goods/Documents/DGR52_PI650_EN.p
df 
 
 

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70 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 3 weeks prior to patient OPEN registration. 
(Patient must start protocol therapy within 7 days after OPEN registration.)  Scans must be done 
<4 weeks prior to the start of therapy.  In the event that the patient’s condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of 
therapy. 
 
 
Pre- 
Study1 
Cycle 
11,2 
D1 
Cycle 
1 
D8 
Cycle 
1 
D9 
Cycle 
1 
D15 
Cycles 
2,4,etc.2   
D1 
Cycle 
2 
D15 
Cycles    
3, 5, etc.2,3 
D1 
Treatment 
Discontin
uation4 
Safety 
Follow-
up5 
Long-
term 
Follow-
up6 
Ibrutinib 
 
Begin 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
History7 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Physical 
Exam8   
X 
X8 
 
 
X 
X 
X 
X 
X 
X 
 
Performance 
Status 
(Appendix A) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
Review 
 
 
 
Review 
 
 
Review 
Review 
 
Serum β-
HCG9 
X9 
 
 
 
 
 
 
 
 
 
 
CBC w/diff 
X 
X 
X19 
 
X 
X 
X 
X 
X 
 
 
Serum 
Chemistries10 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
LFTs11 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Radiographic 
Evaluations 
with Tumor 
Measurements 
X12 
 
 
 
 
 
 
X12 
X12 
 
 
Patient Diary 
(Appendix C) 
X 
Review 
 
 
 
Review 
 
 
Review 
 
 
Toxicity 
Monitoring 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X6 
Request 
Archive Tissue   
 -OR- 
Obtain      
Fresh Tissue 
(correlative) 
X13 
 
 
 
 
 
 
 
 
 
 
PBMC 
(correlative) 
X14, 17 
 
 
 
 
X14 
 
 
X14 
 
 
Plasma 
(correlative) 
X15, 17 
 
 
 
 
X15 
Cycle 2  
 
X15 
X15 
 
 
Whole Blood 
(correlative) 
X16, 17 
 
 
 
 
 
 
 
 
 
 
PK 
(correlative) 
 
X18 
X18 
X18 
 
 
 
 
 
 
 
Survival  
 
 
 
 
 
 
 
 
 
 
X 

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71 
 
Key to Footnotes  
 
1 Pre-study screening evaluations other than imaging must be done within 21 days prior to 
patient OPEN registration. (Patient must start protocol therapy within 7 days after OPEN 
registration.) Imaging studies must be conducted within 28 days prior to Day 1 of ibrutinib.  If 
pre-study screening hematology and serum chemistries were performed within 7 days of Day 1 
of Cycle 1 of treatment, these do not need to be repeated.   
 
2A window of 2 days will be applied to all study visits including treatment; for every other cycle 
tumor imaging, imaging may take place within 7 days prior to the study visit. 
 
3Tumor imaging will continue every other cycle on odd-numbered cycles until progression. 
 
4This visit should occur in patients when treatment stops, for whatever reason (toxicity, 
progression, or at discretion of the investigator). 
 
5Subjects who discontinue therapy will be followed for safety for 28 days (±3 days) following 
the last administration of ibrutinib.   
 
6Patients who have ongoing Grade 4 AE or SAE at the time of discontinuation from treatment, 
and those who come off treatment prematurely for safety reasons will continue to be followed at 
least every 30 days until the event is resolved or deemed irreversible by the investigator. After 
ibrutinib treatment ends, anti-cancer medications taken by the patient should be documented 
every 3 months (± 1 month) in the eCRF if this information is available for up to 2 years or until 
death, whichever comes first.   
 
7Complete medical history at baseline including documentation of BRAFV600 mutation status, 
and documentation of resolution of any toxicities from prior treatment to baseline or ≤Grade 1 
(other than alopecia); thereafter focused history on symptoms/toxicity. 
 
8Physical exam to include height (baseline only), vital signs and weight; repeat physical exam on 
Day 1 of Cycle 1 is at discretion of investigator. 
 
9Serum β-HCG (pregnancy test) will be obtained within 7 days prior to Day 1 of ibrutinib in 
women of child-bearing potential. 
 
10Serum chemistries will be obtained to include Na, K, Cl, Mg, creatinine, BUN, glucose, 
phosphate, calcium. 
 
11Liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase. 
 
12Tumor response assessment will be performed by the investigator via CT scans of neck (if 
applicable), chest, abdomen, pelvis; CT scans will be done at treatment discontinuation 
irrespective of whether clinical progression is suspected by the investigator. If tumor assessments 
are available for patients who have not yet experienced progressive disease (PD) at the time 

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72 
treatment is discontinued, the follow-up tumor evaluations will be documented in the electronic 
case report form (eCRF) until PD or death is confirmed, or until another treatment is initiated. 
 
13Request access to archival tissue (FFPE blocks/slides) to support biomarker studies; consent for 
the use of any residual material from diagnostic biopsy (archival tissue) will be required for 
enrollment.  [NOTE: Investigator must review pathology report to ensure sufficient tumor should 
be available for support of correlative studies; patients with insufficient tissue will NOT be 
eligible for this study].  If sufficient archival tissue is unavailable, a fresh biopsy must be 
obtained and the same rules apply for the fresh biopsy sample i.e., sufficient metastatic tumor 
must be available to support correlative studies. 
 
14Blood for isolation of PBMCs (50 mL total; 10 mL each in 5 tubes) will be collected into 5 
green-top (sodium heparin) tubes at pre-study (i.e., baseline), pre-dose on Day 1 of Cycle 2, and 
at disease progression.  
 
15Blood for plasma (10 mL) will be collected into a lavender-top (K2EDTA) tube at pre-study 
(i.e., baseline), pre-dose on Day 1 of Cycle 2 (i.e., Day 29) at each odd numbered cycle (i.e., at 
each restaging predose on D1 at Cycles 3, 5, etc.), and at disease progression.  
 
16Whole blood (6 mL) will be collected into a pink-top or purple-top (K2EDTA) tube at pre-
study (i.e., baseline) only.  
 
17Pre-study (i.e., baseline) blood for PBMC, plasma, and whole blood may be obtained pre-dose 
on Cycle 1 Day 1.   
 
18Blood (2 mL per sample time point) for plasma isolation will be collected into 2mL plastic 
green-top (sodium heparin) tubes for PK studies. A single sample should be collected on Day 1 
of Cycle 1 before the ibrutinib dose is given. Serial PK samples will be collected on Day 8 of 
Cycle 1 at pre-dose and at 0.5, 1, 2, 4, 6 and 24 hours after ibrutinib administration as outlined in 
table below.   
 
Cycle 
Day 
Predoseb 
(trough 
value) 
Time after dosinga 
 
0.5 h  
± 5 min 
1h 
 ± 15 min 
2 h 
 ± 15 min 
4 h  
± 30 min 
6 h  
± 1 h 
 
24 h 
± 2 h 
1 
8 
x 
x 
x 
x 
x 
x 
xb 
a. 
Record actual time of sample collection 
b. Sample collected 24 hours (± 2 hours) after last intake and prior to dosing on that PK day (ie, 
Cycle 1 Day 8 and Day 9). 
 
 
19A CBC with differential test should be performed on Day 8 of Cycle 1 to monitor for decreases 
in platelet count that may occur during ibrutinib therapy. Typically, thrombocytopenia associated 
with ibrutinib is asymptomatic and resolves without the need for dose adjustment. However, 
dose reduction should be considered if platelet counts do not recover and symptomology related 
to thrombocytopenia develops (e.g., petechiae, frequent nose bleeds, etc.). It is prudent to 

NCI Protocol #: 9922 
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73 
monitor blood counts more closely during the first cycle because the 840 mg dose of ibrutinib 
under study is higher than the approved dose in the label.  There is limited safety information 
available in subjects who have received this higher dose of ibrutinib and data that are available 
reside in patients with hematologic malignancies.   
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (2 
cycles). In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)(Eisenhauer et al., 2009).  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with ibrutinib. 
 
Evaluable for objective response.  Only those patients 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 patients will have their 
response classified according to the definitions stated below.  (NOTE:  Patients who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable, but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20mm (≥2cm) 
by chest x-ray or as ≥10mm (≥1cm) with CT scan, MRI, or calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 

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74 
 
NOTE: Tumor lesions that are situated in a previously irradiated area must not be 
considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm (≥1.5cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5mm [0.5cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10mm [<1cm] or pathological lymph nodes with ≥10 to <15mm [≥1 
to <1.5cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangiitis 
cutis/pneumonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but, in addition, should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion that can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or, in rare cases, unequivocal progression of each should be noted 
throughout follow-up.  
 

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75 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable if they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10mm (≥1cm) diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm (0.5cm) or less.  If CT scans 
have slice thickness greater than 5 mm (0.5cm), the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain situations 
(e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data that may 

NCI Protocol #: 9922 
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76 
bias an investigator if it is not routinely or serially performed.   
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator-dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
(Bubley et al., 1999; Rustin et al., 2004; Scher et al., 2008).  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria, which are to be integrated 
with objective tumor assessment for use in first-line trials in ovarian cancer (Vergote et 
al., 2000). 
 
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 

NCI Protocol #: 9922 
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77 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR, due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
[NOTE:  A ‘positive’ FDG-PET scan lesion means one which is FDG-avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image.] 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 
cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5mm (0.5cm).  [NOTE:  the appearance 
of one or more new lesions is also considered progression.] 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10mm [<1cm] 
short axis). 
 
[NOTE:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.] 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 

NCI Protocol #: 9922 
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78 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
NOTE:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
 
 

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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
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, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from Day 1 of treatment to time of progression 
(based on clinical or radiographic grounds) or death as a result of any cause, whichever 
occurs first.  
 
 
11.1.7 Overall Survival (OS) 
 
OS is defined as the duration of time from Day 1 of treatment to death as a result of any 
cause. 
 
11.1.8 Response Review 
 
N/A 
 
11.2 
Other Response Parameters 
 
N/A 
 

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80 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, routine SAEs; 
reporting of expedited AEs; and accumulation of reported AEs from other trials testing the same 
drug(s).  The Principal Investigator and statistician have access to the data at all times through 
the CTMS web-based reporting portal.   
 
During the Phase 2 portion of the study, the Principal Investigator will have, at a minimum, 
quarterly conference calls with the Study Investigators and the CTEP Medical Officer(s) to 
review accrual, progress, and pharmacovigilance.  Decisions to proceed to the second stage of a 
Phase 2 trial will require sign-off by the Principal Investigator and the Protocol Statistician.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data and Safety Monitoring Plan 
 
The Lead Principal Investigator and co-investigators will provide continuous monitoring of 
patient safety in this trial, including regularly scheduled teleconferences with participating 
ETCTN sites and representatives from CTEP/Pharmacyclics. Summary information regarding 
toxicity and accrual patterns, including information from all multicenter sites participating in the 
trial will be prepared by Lead Principal Investigator or designee. More specifically, the Lead 
Principal Investigator will review all AE data monthly and all grade 4 to 5 AEs weekly and all 
SAEs within 72 hours (or earlier, if required). In addition, the Lead Principal Investigator will 
review all treatment discontinuations and their attribution to the study drug.  
 
Meetings/teleconferences will be held on a bi-weekly basis while the study is enrolling patients. 
These meetings will include the clinical investigators as well as study coordinators, clinical 
research associates, regulatory associates, data managers, a GMP facility representative, 
biostatisticians, and any other relevant personnel the Lead Principal Investigator may deem 
appropriate (e.g. CTEP personnel), including an external experienced investigator (preferably a 
lymphoma specialist with experience in ibrutinib administration) who is not involved in the 
study conduct. The frequency of meetings can change depending on the number of active 

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81 
patients (i.e. once a month if there are no active patients; every 21 days if only one active patient; 
or weekly if >5 active patients remain on study). Ad hoc meetings will be convened if an 
unexpected safety concern is identified during the conduct of the trial.  A table of all AEs to be 
discussed will be shared ahead of the scheduled teleconference. After enrollment is complete, 
meetings will be held monthly until there are no remaining patients on study. During these 
meetings, the research team will discuss all issues relevant to study progress, including topics 
such as enrollment, safety, regulatory, data collection, etc.  Decision options will be: continue as 
is, hold or modify accrual, evaluate AEs in more detail with or without accrual on hold, and/or 
modify monitoring or management plan (including supportive care), amend, or close. The team 
will produce summaries or minutes of these meetings, which will be archived. These summaries 
will be available for inspection when requested by any of the regulatory bodies charged with the 
safety of human patients and the integrity of data for ETCTN trials. 
 
Following accrual of the last patient in stage 1, the study will be suspended for interim analysis 
of the primary (overall response rate) and two of the secondary endpoints (PFS and toxicity). 
During interim analysis all grade 4/5 and SAE rates will be reviewed and a decision regarding 
their attribution to study drug will be resolved by consensus. Suspension can take up to 16 
weeks, in particular if the primary endpoint is not met, and therefore estimation of the 6-month 
PFS endpoint is required for assessment of clinical benefit. See Section 13.2, Sample 
Size/Accrual Rate for details. A meeting will be subsequently convened to discuss results from 
the interim analysis to determine if the trial should be terminated due to lack of efficacy. As 
described above, an agenda and minutes will be generated to document attendees and the 
outcome of the interim analysis. 
 
12.3 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on either the 
LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab 
Admin role, the user must hold a minimum of an AP registration type.  To hold the Rave Site Investigator 
role, the individual must be registered as an NPIVR or IVR.  Associates can hold read-only roles in Rave.  
If the study has a DTL, individuals requiring write access to Rave must also be assigned the appropriate 
Rave tasks on the DTL.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 

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82 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.3.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available 
at:http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  
On-site audits will be conducted on an 18-36 month basis as part of routine cancer center 
site visits. More frequent audits may be conducted if warranted by accrual or due to 
concerns regarding data quality or timely submission.  For CTMS monitored studies, 
after users have activated their accounts, please contact the Theradex Help Desk at (609) 
799-7580 or by email at  CTMSSupport@theradex.com for additional support with Rave 
and completion of CRFs. 
 
12.3.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol-specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent, if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
) and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 

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83 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included, when appropriate, to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
 
12.4 
CTEP Multicenter Guidelines 
 
N/A 
 
12.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 

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84 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used, and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the Principal Investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 

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85 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This will be an open label, single arm, phase 2 study of patients who have failed, or are not 
eligible for, all other prior systemic FDA-approved treatments for metastatic melanoma.  The 
primary endpoint will be assessment of antitumor response, defined as the sum of complete 
response and partial response evaluated by RECIST criteria 1.1 every two cycles (8 weeks) as 
assessed by the investigator.  Secondary clinical endpoints include estimates of PFS at 6 months, 
OS at 1 year, and toxicity assessment.  Another secondary objective is to explore the association 
of ITK protein expression with OR and PFS. The ITK protein expression in melanoma cells at 
pretreatment will be assessed by 2-color immunofluorescence (IF) in representative tissue 
sections obtained from archival formalin-fixed embedded blocks or in representative tissue 
sections/slides obtained from fresh biopsies from enrolled patients. Exploratory endpoints 
include protein expression of putative targets of ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK) in 
melanoma cells assessed by 2-color immunofluorescence (IF) in representative tissue sections 
obtained from pretreatment archived formalin-fixed paraffin-embedded (FFPE) tumor blocks or 
from FFPE blocks prepared from fresh biopsy tissue from enrolled patients, with OR and without 
progression, multiparameter flow cytometric endpoints in PBMC obtained prior to treatment, on 
day 29 following initiation of treatment with ibrutinib, and at the time of disease progression (3 
time points). 
 
13.2 
Sample Size/Accrual Rate 
 
Our null hypothesis is that the true antitumor response rate is 5%, as per the response rate seen in 
patients who were treated with investigators’ choice chemotherapy as part of the recent study of 
PD-1 inhibitors for patients with ipilimumab-refractory, BRAF inhibitor-refractory (if 
BRAFV600-mutant) metastatic cutaneous melanoma (Ribas et al., 2015; Weber et al., 2015), 
against an one-sided alternative. The assessment of objective response at interim and final 
analysis will be based upon investigator’s assessment of response. We will use Simon’s two-
stage design. In the first stage, 18 patients will be accrued and study will be suspended for up to 
16 weeks for interim analysis. If there are no antitumor responses in these 18 patients, then we 
will assess the 6-month PFS rate. In the 6-month PFS rate scenario the null hypothesis is that 
ibrutinib is not effective if the 6-month PFS rate is 18% and the alternative hypothesis is that 
ibrutinib is promising if the 6-month PFS rate is 35%. The null and alternative hypotheses 
scenarios for the 6-month PFS rate are based on the KEYNOTE-006 trial in which the 6-month 
PFS rate for the investigators’ choice chemotherapy versus the pembrolizumab arm was 16% 
versus 34% (Ribas et al., 2015).  
 
If either the antitumor response and/or the 6-month PFS rate endpoint are met then 14 additional 
patients will be accrued for a total of 32. The null hypothesis will be rejected if 4 or more 
responses are observed in 32 patients. This design yields a type I error rate of 0.1 and power of 
90% when the true response rate is 0.2. If the null hypothesis for the antitumor response endpoint 
is not met, then we will investigate the 6-month PFS rate endpoint. The Simon’s design would 
reject the null if 9 or more patient out of 32 have PFS better than 6 months. 
 

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13.3 
Toxicity Assessment 
The phase 1 dose escalation study of ibrutinib in patients with CLL showed that both the safety 
and efficacy are similar for this population irrespective of the dose cohort (420mg versus 
840mg)(Byrd et al., 2013). Nevertheless, it is possible that there may be higher rates of AEs 
from ibrutinib treatment for a solid tumor malignancy, such as melanoma. Continuous toxicity 
monitoring will be performed based on the data and safety monitoring plan described in section 
12.1. More specifically, sequential boundaries will be used to monitor the high grade AE rate, 
defined as all grade 3/4/5 events attributed to the ibrutinib. The accrual will be halted if 
excessive numbers of study drug-related high grade AEs or SAEs are seen, that is, if the number 
of patients with at least one AE grade 3/4/5 is equal to or exceeds bn out of n patients with full 
follow-up (see table below). This is a Pocock-type stopping boundary that yields the probability 
of crossing the boundary at most 0.1 when the AE rate for grade 3/4/5 events is equal to the 
acceptable rate of 0.38. The 38% acceptable grade 3/4/5 AE rate is based on the recent phase III 
study of ibrutinib (560mg) versus temsirolimus in patients with relapsed or refractory mantle cell 
lymphoma(Dreyling et al., 2016). 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- - - 4 5 5 6 7 7 8 8 9 9 10 10 11 11 12 12 13 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
13 14 14 14 15 15 16 16 17 17 18 18  
 
 
 
 
 
 
 
 
A separate boundary will be used to monitor the rate of thrombocytopenia and hemorrhagic 
events attributed to the study drug. The accrual will be halted if excessive numbers of these 
events are seen; that is, if the total number of patients with at least one Grade 3/4/5 
thrombocytopenia or hemorrhagic event is equal to or exceeds bn out of n patients with full 
follow-up (see table below). This is a Pocock-type stopping boundary that yields the probability 
of crossing the boundary at most 0.1 when the rate of high grade thrombocytopenia and 
hemorrhagic events is equal to the acceptable rate of 0.09, as recently reported (Dreyling et al., 
2016): 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- 2 2 3 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
5 5 6 6 6 6 6 6 6 7 7 7  
 
 
 
 
 
 
 
 
We anticipate accruing 3 patients/month across the UM1 consortium. 
 
Below are estimates of accrual for this trial. These estimates are based on Cancer Facts & 
Figures 2015(Siegel et al., 2015) and experience at a tertiary care center. Cutaneous melanoma is 
most common in non-Hispanic whites, so we expect this to be the largest group of patients in this 
trial. We anticipate accruing at least a few black and Hispanic patients, however, and every effort 
will be made to include all minority groups. While incidence of cutaneous melanoma is similar 
between men and women, mortality is higher for men. Given that this trial enrolls patients with 
refractory metastatic disease, we anticipate enrolling more men than women into the study. 

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87 
 
 
 
 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
1 
0 
0 
2 
White 
9 
16 
1 
3 
29 
More Than One Race 
0 
1 
0 
0 
1 
Total 
10 
18 
1 
3 
32 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
 
OMB No. 0925-0001/0002 
 
13.4 
Stratification Factors 
 
N/A 
 
13.5 
Analysis of Primary Endpoint 
 
We will compute point estimate and 95% confidence interval for antitumor response. 
 
13.6 
Analysis of Secondary Endpoint 
PFS and OS will be estimated using the Kaplan Meier method. To explore the association of a 
baseline ITK protein expression in melanoma cells with OR, we will compute the mean ITK 
protein expression in patients with CR, PR, SD and PD, and perform the Jonckheere–Terpstra 
test for trend. To explore the association of a baseline ITK protein expression with PFS, we will 
compute the mean ITK protein expression in patients with PFS less than 6 months and longer 
than 6 months. We will also fit a Cox model with ITK protein expression as a continuous 
covariate.   
 
 

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13.7 
Analysis of Exploratory Endpoints 
 
The protein expression levels of ITK and various putative targets of ibrutinib in melanoma cells 
from pretreatment archived FFPE tumor blocks or from FFPE blocks prepared from fresh biopsy 
will be assessed 2-color IF, and analyzed by Aperio imaging, as we have previously published 
(Schlegel et al., 2013; Nikolaishvilli-Feinberg et al., 2014; Carson et al., 2015). Briefly, the 
Color Deconvolution v9 area quantification algorithm (ImageScope) software will be used to 
calculate the average H-score for each stain and for the cells of interest (S100+). To investigate 
the predictive ability of protein expression measured by H-score (continuous variable) as a 
predictor or antitumor response or PFS to ibrutinib. Exploratory analysis will also be performed 
to assess the predictive ability of each tissue biomarker by fitting logistic model or Cox model 
with biomarker as a covariate. For the latter analysis, antitumor response rate or PFS information 
will be used to investigate possible cut-points for the biomarker.  
 
PBMC from three different time points (baseline, Day 29, and at disease progression) will be 
stained for various immune regulatory cell populations, as well as markers for Th1 and Th2 
responses. Within-patient changes in the expression of particular immune cell subsets in samples 
taken   prior to study treatment, day 29 (i.e., predose D1 of cycle 2), and at disease progression 
will be assessed by comparisons using ANOVA followed by paired t-test or other tests 
(Wilcoxon rank-sum test), if normality assumption is not satisfied even when data transformation 
is performed. Within-patient changes in peripheral blood will be characterized for patients who 
respond to treatment and for those who do not.  
 
Non-compartmental pharmacokinetic (PK) analysis will be performed on ibrutinib (PCI-32765) 
concentrations in plasma using WinNonlin.  The following parameters will be estimated: 
maximum concentration (Cmax), time of maximum concentration (Tmax), area under the 
concentration verses time curve (AUC), half-life (t½), apparent clearance (CL), apparent volume 
of distribution (Vd).  The PK from this study will be compared to the prior study of ibrutinib 
(PCI-32765) at the lower dose of 560 mg. 
 
13.8 
Reporting and Exclusions 
 
13.8.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
ibrutinib.  
 
13.8.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [NOTE:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 

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All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) will be included in the main analysis of the response 
rate.  Patients in response categories 4-9 should be considered to have a treatment failure 
(disease progression).  Thus, an incorrect treatment schedule or drug administration will 
not result in exclusion from the analysis of the response rate. Subanalyses of the patients 
who have received at least one cycle (4 weeks) of ibrutinib therapy will be also 
undertaken.  
  
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

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APPENDIX B 
ADEQUACY OF ARCHIVED/FRESH TUMOR TISSUE  
 
Below is a sample letter from the pathologist stating the adequacy of archived or fresh tumor 
tissue for tumor imaging analysis.  
 
 
Stergios Moschos 
University of North Carolina at Chapel Hill 
Department of Medicine, Division of Hematology/Oncology 
Physician’s Office Building, Suite 3116-CB#7305 
170 Manning Drive 
Chapel Hill, NC 27599 
Phone (O): 919-843-7713 
Cell: 412-915-5014 
Fax: 919-966-6735 
E-mail: Stergios_moschos@med.unc.edu 
 
 
Dear Dr. Moschos, 
 
I have reviewed the hematoxylin and eosin stained slides corresponding to [SCREENING 
SUBJECT ID NUMBER and SUBJECT INITIALS]’s archived or fresh tumor block from the 
[PATIENT’S SURGICAL PROCEDURE TYPE]. I have confirmed that the amount and quality 
of remaining tumor tissue material contained in this block is sufficient to generate 11 (min) to 15 
(max) 5-micron blank sections for histopathologic analysis. 
 
I will release 11-15 5-micron tissue sections on charged slides to your institution for 
research analysis. 
 
I will release the entire paraffin block to your institution for research analysis. 
 
 
Please return the paraffin block (if the paraffin block checkbox is checked off) to the mailing 
address noted in this letter.  
 
 
Sincerely, 
 
[INSTITUTION PATHOLOGIST SIGNATURE] 
[PRINTED NAME AND MAILING ADDRESS] 
 
 

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Below is a sample documentation from the Lead Principal Investigator stating the adequacy of 
archived tissue ONLY.  
 
 
PARTICIPATING INSTITUTION_______________________________________________ 
 
Screening Subject ID #: __________________   Subject Initials: _____  , _____   _____ 
 
 
 
 
 
                                                Last,        First        Middle 
 
Site Name: _____________________   Site Contact Person Name: _____________________ 
 
Site Contact Person Email: _____________________________________________________  
   
Pathology materials provided (check appropriate box): 
 
Slides 
 
De-identified pathology reports 
 
Digital images 
 
 
 
 
LEAD PRINCIPAL INVESTIGATOR ____________________________________________ 
 
Dr. Stergios Moschos has reviewed the above materials provided and has determined that 
[SCREENING SUBJECT ID NUMBER and SUBJECT INITIALS] (check appropriate box): 
 
Adequate tissue is available to confirm eligibility   
 
Insufficient tissue is available to confirm eligibility (provide comments): 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
______________________________ 
Lead Principal Investigator Signature                                     Date  
 

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APPENDIX C 
PATIENT DIARY FOR IBRUTINIB 
PATIENT DIARY FOR IBRUTINIB 
 
Subject ID Number: _____                                 Cycle #_____     
             
Time Period:             From                     /                  to       /           /         
 
 
                                  month                  day                 year                            month              day                    year 
 
Patient Instructions: Use this calendar as a reminder to take your medication every day. Be 
sure to write the number of capsules taken each time. Start recording your first day of taking 
pills in the first box (DAY 1). Be sure to bring this calendar and the mediation bottle with you 
for all of your return appointments. Thank you. 
• Take each dose of ibrutinib capsules (# __ of 140 mg capsules = _____ mg) once daily by 
mouth. 
• Swallow the capsules whole with water (use a glass (8 ounces, 1cup) of water total for 
each _____ mg dose).  
• Take each dose at approximately the same time each day. 
• Fish oil and vitamin E products should not be taken while taking ibrutinib 
• Ibrutinib must not be taken with grapefruit juice. 
• Do not open, break or chew capsules, and do not attempt to dissolve them in water. 
• 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. Extra capsules should not be 
taken to make up for the missed dose.  
• If you vomit immediately after taking your dose, do not replace this dose. Continue dosing 
the next day as per usual. Record the vomiting episode on your medication diary.  
• Return any remaining ibrutinib capsules to research staff once treatment is complete, and 
as per study instructions. 
 
 
START 
HERE 
DAY 1 
DAY 2 
DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
# capsules__ 
Time:_____ 
 
Returned Pill Count:               Subject Signature:                                           Date:_____________    
 
Site Personnel Signature:                                                                                Date:_____________ 

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APPENDIX D 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent ibrutinib.  This clinical trial is sponsored by the National Cancer Institute.  
This form is addressed to the patient, but includes important information for others who care for 
this patient.  
 
Ibrutinib interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
• Ibrutinib is metabolized by a certain specific enzyme in your liver.  
• The enzyme in question is the CYP3A enzyme and ibrutinib is broken down by this 
enzyme in order to be cleared from your system. 
• Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding 
or removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors of the CYP3A 
isoenzyme. 
• Your prescribers should look at this web site 
http://medicine.iupui.edu/CLINPHARM/ddis/main-table 
or consult a medical reference to see if any medicine they want to prescribe is on a list of 
drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it is usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
• Be careful:  
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
101 
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking ibrutinib.  
• Other medicines can be a problem with your study drugs.  
• You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.   
• Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is 
___________________________________ and he or she can be contacted at 
_____________________________________. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines 
that interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP______.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/ for a list of drugs 
to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
102 
APPENDIX E 
ARCHIVAL/FRESH TISSUE SUBMISSION FORM 
 
 
NCI9922 Archival/Fresh Tissue Block/Slides Submission Form 
 
 
Subject ID #: ________________________   Subject Initials: _____ , _____   _____ 
 
 
 
 
 
 
                                            Last,            First           Middle 
 
Site Name: ___________________________ Contact Person: ________________________________ 
 
Phone: _______________________________ Email: ________________________________________ 
 
Date Shipped: _________________  Courier/Airbill Tracking #: ____________________________ 
 
Date of Biopsy 
(mm/dd/yyyy) 
Type of 
Submission 
Number of 
Slides/Blocks 
Accession 
Number 
Comments 
Tissue 
Type 
Metastatic Site 
(eg, liver, LN etc) 
 
 
  Blocks 
    
  Slides 
 
 
 
 
  Archive 
    
  Fresh 
 
 
Shipping Address: 
 
Mei Huang, Lab Manager 
c/o Tissue Procurement Facility 
108 MacNider Building, CB 7304 
University of North Carolina 
333 South Columbia St 
Chapel Hill, NC 27599 
Phone: 919-966-2620 / Fax: 919-843-9501 
Email: mei_huang@med.unc.edu 
unc_tpf@med.unc.edu 
 
 
 
FOR RECEIVING LABS ONLY 
 
 
Date Received 
Confirmed by 
Comments 
Archival Tissue  
 
 
 
Fresh Tissue 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
103 
APPENDIX F 
CHILD-PUGH SCORE 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964. pp. 50-64.   
Pugh RN, Murray-Lyon IM, Dawson L, et al . “Transection of the oesophagus for bleeding 
oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 
 
 
 
 
 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
104 
APPENDIX G 
PBMC SHIPMENT LOG  
 
               Duke-UNC-Washington University (DUNCWU) 
                          An Early Therapeutics Clinical Trials Network (ETCTN) Partnership 
 
                                                                                NCI9922 PBMC Shipment Log  
Site Name: ___________________________________________  
Date of Shipment:  ______________________  FedEx     ⃞ UPS     ⃞  Other: __________ 
Shipment Tracking Number: ____________________________ 
Insert copy of log with shipment and notify lab of incoming shipment via 9922 Study Portal. 
(Ship to UNC: Patricia Basta - address provided in Section 9.4.1.3 of protocol) 
Subject 
ID# 
Collection Date 
(mm/dd/yyyy) 
Study Visit 
(Prestudy, Day 29 i.e., predose D1 of  
Cycle 2, Disease Progression) 
 
Number(s) of 
Tubes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page __ of __ 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
105 
APPENDIX H 
BIOMARKER SHIPMENT LOG  
 
              Duke-UNC-Washington University (DUNCWU) 
                          An Early Therapeutics Clinical Trials Network (ETCTN) Partnership 
 
                          NCI9922 Biomarker (Whole Blood or Plasma) Shipment Log 
Site Name: ___________________________________________  
Date of Shipment:  ______________________  FedEx     ⃞ UPS     ⃞  Other: __________ 
Shipment Tracking Number: ____________________________ 
Insert copy of log with shipment and notify lab of incoming shipment via 9922 Study Portal. 
(Ship to Duke: Andy Nixon - address provided in Section 9.4.2.3 of protocol)  
Subject 
ID# 
Collection Date 
(mm/dd/yyyy) 
Study Visit 
[Prestudy, predose on 
Day 1 Cycle 2 (Day 29), 
predose  at odd number 
Cycle# Day#, or Disease 
Progression] 
Sample Type 
(plasma or whole 
blood) 
 
Number(s) of 
Tube/Cryovials 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page __ of __ 

NCI Protocol #: 9922 
Version Date:  May 8, 2018  
 
106 
APPENDIX I  
PK SUBMISSION FORM 
 
NCI 9922 Pharmacokinetics Sample Submission Form 
Please include a completed submission form for each sample in with every shipment.   
If a sample was not collected, please give reason in comment box below. 
Pharmacokinetic  
Time points 
Day/Cycle 
Projected 
Obtained 
Problems/ 
Comments 
Date  
(m/d/yy) 
Time 
Date  
(m/d/yy) 
Time 
Pre-dose 
D1/Cycle 1 
 
 
 
 
 
 
Pre-dose 
D8/Cycle 1 
 
 
 
 
 
0.5 hour ±5min  
Post-dose D8/Cycle 1 
 
 
 
 
 
1 hour ±15min  Post-
dose D8/Cycle 1 
 
 
 
 
 
 
2 hours ±15min Post-
dose D8/Cycle 1 
 
 
 
 
 
 
4 hours ±30min Post-
dose D8/Cycle 1 
 
 
 
 
 
 
6 hours ±1 hr  Post-
dose D8/Cycle 1 
 
 
 
 
 
 
24 hours ±2 hr Post-
dose D8/Cycle 1 
 
 
 
 
 
Send all specimens on dry ice by a courier guaranteeing overnight delivery to the following address:    
 
 
Mei Huang, Lab Manager 
c/o Tissue Procurement Facility 
108 MacNider Building, CB 7304 
University of North Carolina 
333 South Columbia St 
Chapel Hill, NC 27599 
Phone: 919-966-2620 / Fax: 919-843-9501 
Email: mei_huang@med.unc.edu Lab email: unc_tpf@med.unc.edu 
 
FOR RECEIVING LABS ONLY 
 
Date Received 
Confirmed by 
Comments 
Pharmacokinetics  
 
 
 
 
Subject ID: ___________________  Subject’s Initials: _______ ,  ________   ________ 
 
 
 
 
 
 
 
         Last,  
    First                 Middle 
 
Site: _______________________ Contact Person: ____________________________ 
 
Phone:  ___________________________ Email: _____________________________ 
 
FedEx/UPS Tracking #: _______________________ Date Shipped:_______________