Clinical trial NCT02575300
Conditions: Carcinoid Tumors Pancreatic NET
Keywords: neuroendocrine tumors (NETs) gastroenteropancreatic NETs pancreatic NETs gastrointestinal (GI) tract NET advanced carcinoid tumors
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2015-10-09; Completion date: 2019-11-04
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective phase II open-label trial, stratifying patients equally into two cohorts consisting of carcinoid tumors and pancreatic neuroendocrine tumors (pNETs). The purpose of this study is to test any good and bad effects of the study drug called Ibrutinib.

The study population will consist of adult patients with histologically confirmed low to intermediate grade NETs of the GI tract, lungs and unknown primary (carcinoid tumors) or pNETs. All patients must be confirmed to have advanced disease. The study will enroll up to 51 patients in two cohorts (30 carcinoid and 21 pNET patients).

Detailed description:

Arms: arm 1: Ibrutinib Initial Dose 560 mg by mouth (PO) every day (QD)
Interventions: intervention 1: Ibrutinib
Intervention descriptions: intervention 1: Ibrutinib will be administered orally once daily and each cycle will be defined as 4 weeks duration. Study treatment should begin within 14 days following enrollment into the study and continue until disease progression, unacceptable toxicity, or withdrawal of consent.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Phase II Study of Ibrutinib in Advanced Carcinoid and 
Pancreatic Neuroendocrine Tumors 
 
 
NCT02575300 
 
Version 2.0 
January 7, 2016 


1 
 
Medical Affairs 
Ibrutinib 
Clinical Trial Protocol … 
 Phase II Study of ibrutinib in advanced carcinoid and 
pancreatic neuroendocrine tumors 
Author: 
Jonathan Strosberg, MD 
Version number: 
2.0 
 
Release date: 
 01/07/2016 
V1.1 03/24/2015 
 
Principal Investigators: 
 
Jonathan Strosberg, MD 
H. Lee Moffitt Cancer Center,  
12902 Magnolia Dr. 
Tampa, FL 33612 
jonathan.strosberg@moffitt.org 
Phone: 813-745-7257 
Fax:  813-745-7229 
 
 
 
Statistician:  
Michael Schell, PhD 
H. Lee Moffitt Cancer Center,  
12902 Magnolia Dr. 
Tampa, FL 33612 
Michael.schell@moffitt.org 
Phone: 813-745-6061 


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Fax:  813-745-5855 
 
 


3 
 
Table of contents 
Table of contents 2 
List of tables 
 ............................................................................................................................ 4 
List of abbreviations ......................................................................................................................... 5 
 1 
Background .......................................................................................................................... 6 
 
1.1 
Overview of neuroendocrine tumors ................................................................... 6 
 
1.2 
Mast cells as a target for NET therapy ................................................................ 7 
 
1.3 
Ibrutinib............................................................................................................... 7 
     1.3.1 Ibrutinib preclinical experience. ......................................................................... 7 
      
1.3.1.1 Pharmacodynamics ................................................................................. 8 
 
1.3.1.2 Pharmacokinetics .................................................................................... 9 
 
1.3.1.3 Toxicology .............................................................................................. 9 
     1.3.2 Ibrutinib clinical experience. ............................................................................... 9 
  
    1.3.2.1 Pharmacokinetics. ............................................................................... 9 
  
   1.3.2.2 Ibrutinib in healthy volunteers. .......................................................... 10 
 
   1.3.2.3. Ibrutinib in mantle-cell lymphoma ................................................... 10 
 
   1.3.2.4 Ibrutinib in chronic lymphocytic leukemia. ....................................... 11 
 
   1.3.2.5 Ibrutinib in other hematological malignancies. ................................. 11 
     1.3.3 Summary of Clinical Safety of ibrutinib. .......................................................... 12 
 
    1.3.3.1 Treatment Discontinuations. ............................................................. 12 
 
 1.3.3.2 Cytopenias ......................................................................................... 12 
 
 1.3.3.3 Diarrhea ............................................................................................. 12 
 
    1.3.3.4 Hemorrhagic Events. ......................................................................... 12 
 
    1.3.3.5 Cardiac. ............................................................................................. 13 
 
    1.3.3.6 Rash. .................................................................................................. 13 
 
    1.3.3.7 Other malignancies............................................................................ 13 
 
    1.3.3.8 Infection. ........................................................................................... 13 
1.4 
Study rationale. ................................................................................................. 13 
2 
Study objectives ................................................................................................................. 14 
 
2.1 
Selection of doses ............................................................................................. 14 
3 
Endpoints ............................................................................................................................ 14 
 
3.1 
Primary endpoints ............................................................................................. 14 
 
3.2 
Secondary endpoints ......................................................................................... 14 
 
3.3 
Exploratory endpoint ........................................................................................ 14 
4 
Investigational plan ............................................................................................................ 15 
 
4.1 
Overall study design ......................................................................................... 15 
 
4.2 
Treatment .......................................................................................................... 15 
 
4.3 
Study population ............................................................................................... 15 
 
4.4 
Inclusion/exclusion criteria ............................................................................... 15 
 
     4.4.1 Inclusion criteria ............................................................................................... 15 


4 
 
 
     4.4.2 Exclusion criteria .............................................................................................. 16 
 
4.4.3 Definition of childbearing potential .................................................................... 17 
 5 
Study medication ................................................................................................................ 17 
 
5.1 
Study drug: Ibrutinib ......................................................................................... 17 
  
5.2 
Dose modifications ........................................................................................... 18 
 
5.2.1 Dose modifications for hepatic impaired subjects .............................................. 18 
 
5.3 
Concomitant therapy ......................................................................................... 19 
 
     5.3.1 Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ....... 19 
 
    5.3.1.1 QT prolonging agents. ....................................................................... 20 
 
    5.3.1.2 Antiplatelet Agents and Anticoagulants. ........................................... 20 
 
5.4 
Interruption of discontinuation of treatment ..................................................... 20 
 
5.5 
Guidelines for Ibrutinib Management with Surgeries or Procedure ................. 20 
 
     5.5.1 Minor Surgical Procedures................................................................................ 20 
 
     5.5.2 Major Surgical Procedures ................................................................................ 21 
 
     5.5.3 Emergency procedures ...................................................................................... 21 
 6 
Visit schedule and assessments .......................................................................................... 21 
  
6.1 
Pretreatment evaluation..................................................................................... 21 
 
6.2 
Evaluations during treatment ............................................................................ 22 
 
6.3 
Instructions for processing correlative laboratory studies ................................ 22 
 
     6.3.1 Blood-based biomarkers ................................................................................... 22 
 
 
6.3.2  Tissue-based biomarkers .................................................................................... 23  
 
6.4 
Evaluation schema ............................................................................................ 23 
7 
Outcome Measures ............................................................................................................. 25 
 
7.1 
RECIST criteria for response ............................................................................ 25 
 
7.1.1 Evaluation of target lesions ............................................................................... 26 
7.1.2 Special notes on the assessment of target lesions ............................................. 26 
7.1.3 Evaluation of non-target lesions ....................................................................... 27 
7.1.4 New lesions ....................................................................................................... 27 
7.1.5 Evaluation of response ...................................................................................... 28 
 
7.2 
Guidelines for evaluation of measureable disease ............................................ 29 
 
7.3 
Confirmation of Measurement/Duration of Response ...................................... 30 
8 
Statistical considerations .................................................................................................... 30 
 
8.1 
Sample size ....................................................................................................... 30 
 
8.2 
Endpoints to be followed .................................................................................. 31 
 
8.3 
Sample size calculation ..................................................................................... 31 
 
8.4 
Replcacement of dropouts ................................................................................. 32 
9 
Safety assessments ............................................................................................................ 32 
 
9.1 
Adverse events .................................................................................................. 32 
 
9.1.1 
Attribution ......................................................................................................... 33 
 
9.2 
Adverse events of special interest (AESI) ........................................................ 33 


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9.2.1  Major Hemorrhage ............................................................................................ 34 
9.2.2  Intracranial hemorrhage .................................................................................... 34 
9.3 Serious adverse events ................................................................................................. 34 
 
     9.3.1 SAE definition .................................................................................................. 34 
 
     9.3.2 SAE reporting period ........................................................................................ 35 
 
9.4 
Pregnancy .......................................................................................................... 35 
 
9.5 
Data safety monitoring plan .............................................................................. 35 
10 
Data collection .................................................................................................................... 35 
11 
Quality of life assessment ................................................................................................... 35 
12 
Publication of trial results ................................................................................................... 36 
13 
Regulatory considerations .................................................................................................. 36 
 
13.1 
Protocol review and amendments ..................................................................... 36 
 
13.2 
Informed consent .............................................................................................. 36 
 
13.3 
Committees  ...................................................................................................... 37 
 
 
13.3.1Scientific Review Committee (SRC) ................................................................. 36 
 
13.3.2 Data Safety Monitoring Committee (DSMC) ................................................... 37 
 
13.3.3 Protocol Monitoring Committee (PMC) ........................................................... 37 
 
13.4 
Internal Monitoring ........................................................................................... 37 
 
13.5 
Ethics and Good Clinical Practice .................................................................... 37 
 
13.6 
Declaration of Helsinki ..................................................................................... 37 
 
13.7 
Study documentation ........................................................................................ 38 
 
13.8 
Retention of records .......................................................................................... 38 
14 
References  ......................................................................................................................... 38 
Appendix A ..................................................................................................................................... 42 
Appendix B ...................................................................................................................................... 43 
Appendix C ...................................................................................................................................... 45 
List of tables 
Table 1-3-1-1:  
Median IC50 Values of Ibrutinib Toward Selected Tec and Src/Ab1 Family 
Kinases .............................................................................................................. 8 
Table 5-2:   
Recommended dose modifications for ibrutinib ............................................. 18 
Table 6-5 
Visit evaluation schedule ................................................................................. 23 
Table 7-1-5-1 
Evaluation of best overall response ................................................................. 28 
Table 7-1-5-2 
Evaluation of best overall response in patients with measurable disease ........ 29 


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List of abbreviations  
5-HIAA 
Urinary 5-hydroxyindole acetic acid 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT 
BG 
Blood Glucose 
CPO 
Clinical Pharma Organization 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CT 
Computer Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DM 
Diabetes Mellitus 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practices 
GEP 
Gastroenteropancreatic 
GI 
Gastrointestinal 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
IM 
Independent Ethics Committee 
Intramuscular 
ITT 
Intent to Treat 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
LAR 
Long Acting Release 
MRI 
Magnetic Resonance Imaging 
MTD 
PFS 
Maximum tolerated dose 
Progression-Free Survival 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
SSA 
Somatostatin Analog 
SOP 
Standard Operating Procedure 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
 
 
 
 
 
 


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1. Background 
1.1 
Overview of Neuroendocrine Tumors 
Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by a 
relatively indolent rate of growth and a propensity to produce and secrete a variety of hormones, 
biogenic amines and other vasoactive peptides. Although they may arise in a variety of organs, 
NETs predominate within the pancreas (pNETs) and the gastrointestinal (GI) tract (carcinoids), 
where they originate from the islets of Langerhans and endocrine (enterochromaffin) cells, 
respectively1. 
Carcinoid tumors have distinct clinical features depending on their site of origin. In fact, based 
on their embryologic derivation, NETs are often subclassified as foregut (bronchial, stomach, 
duodenal), midgut (jejunal, ileal, cecal, appendiceal) and hindgut (distal colon and rectal) 
tumors2. While hindgut carcinoid tumors are rarely associated with a hormonal syndrome, 
metastatic midgut carcinoid tumors usually produce serotonin and other vasoactive substances 
which give rise to the typical carcinoid syndrome3. This syndrome primarily manifests as 
diarrhea and flushing, a vasomotor phenomenon which causes redness and warmth in the face 
and upper torso. Carcinoid heart disease, characterized by fibrosis of the tricuspid and pulmonic 
heart valves, can also occur in patients with severe and prolonged elevation of circulating 
serotonin. Tumor growth rates also correlate with site of origin. In the metastatic setting, midgut 
carcinoid tumors tend to behave in the most indolent fashion, whereas NETs originating in the 
foregut or hindgut regions tend to behave more aggressively once they have metastasized. 
pNETs can secrete peptide hormones including insulin, gastrin, glucagon and vasoactive 
intestinal peptide (VIP). However, most pNETs are unassociated with a hormonal syndrome and 
are therefore termed “nonfunctioning”3. 
Recent epidemiological data suggest a rising incidence of NETs and increased survival durations 
over time, but the long-term outcome of patients with advanced-stage disease still remains poor4-
7.  Although historically perceived as similar entities, it is increasingly clear that low- and 
intermediate-grade pNETs and carcinoid tumors have different biology and respond differently 
to therapeutic agents. Carcinoid tumors are relatively insensitive to conventional chemotherapy 
and have no established treatment other than somatostatin analogs (SSAs)8. Initially developed to 
palliate hormonal symptoms, SSAs such as octreotide and lanreotide have been also shown to 
slow tumor progression in patients with advanced carcinoid tumors. In fact, the randomized 
phase III PROMID trial evaluated octreotide long-acting repeatable (LAR) versus placebo in 
patients with metastatic midgut NETs and demonstrated a significant improvement in time-to-
progression9. More recently, the CLARINET trial randomized patients with hormonally 
nonfunctioning gastroenteropancreatic NETs to receive depot-lanreotide versus placebo, also 
demonstrating a statistically significant improvement in progression-free survival (PFS)10. 
pNETs appear to be more sensitive to cytotoxic chemotherapy11, however there are no placebo-
controlled chemotherapy trials and the role of cytotoxic drugs remains controversial. Approved 
treatment agents for pNETs include everolimus and sunitinib. The mTOR inihibitor everolimus 
was recently found to significantly prolong PFS in patients with advanced pNETs12. A 
randomized phase III trial of sunitinib, a multitargeted tyrosine kinase inhibitor, in pNETs 
demonstrated significant improvement in PFS from 5.5 months on the control arm to 11.4 


8 
 
months on the experimental arm13. Despite these encouraging results in terms of PFS 
prolongation, tumor regression is uncommon with targeted agents and no overall survival benefit 
has been demonstrated14. 
Although impressive progress in the biotherapy field has been made over the last decade, no 
proven therapeutic options for patients progressing on initial therapy are currently available and 
response to second line therapies is poorly documented, as demonstrated by lack of 
recommendations from recent consensus statements5. Therefore, there is an urgent need for new 
and effective agents for both carcinoids and pNETs, and novel cellular and molecular targets 
needs to be exploited. 
1.2  
Mast cells as a target for NET therapy 
Although often regarded as a host defensive response to the tumor, inflammation has been 
recently qualified as a collateral consequence of the extensive tissue remodeling that tumor cells 
mediate within their microenvironment via inflammatory cells such as macrophages, neutrophils, 
lymphocytes and mast cells15. Consistent with this idea, many studies have demonstrated that 
expansion and maintenance of macroscopic tumors is highly dependent on the actions of 
inflammatory cells. Recently, chronic activation of Myc in a mouse model of pancreatic β–cell 
tumorigenesis has been reported to be sufficient to initiate and orchestrate a complex 
inflammatory and angiogenic response, characterized by a rapid influx of mast cells into the 
tumor and its adjacent mesenchyma. Furthermore, mast cell recruitment has been described as 
essential for tumor angiogenesis and macroscopic expansion16. Thus, inflammation has been 
proposed as an “oncogene’s weapon” crucial for the development of insulinomas. Mast cells, in 
particular, have emerged as putative targets for NET therapy. 
Reportedly16, systemic treatment of mice harboring islet–cell tumors with the mast cell inhibitor 
sodium chromoglycate induces rapid onset of hypoxia and extensive death of tumor and 
endothelial cells, leading to tumor regression. However in humans, sodium chromoglycate has 
poor systemic bioavailability. Thus, more systemically effective and tolerable inhibitors of mast 
cell function should be tested in clinical trials. 
1.3 
Ibrutinib 
Ibrutinib is a novel first-in-class, orally administered, covalent inhibitor of Bruton’s tyrosine 
kinase (Btk). Its chemical name is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and the molecular weight is 440.50 g/mole. 
Ibrutinib is currently approved for patients with mantle cell lymphoma or chronic lymphoid 
leukemia (CLL) who have received at least one prior therapy and in patients with CLL with 17p 
deletion. 
1.3.1 Ibrutinib preclinical experience 
In preclinical models, ibrutinib has been shown to covalently bind to a cysteine residue (Cys-
481) in the Btk active site, thus resulting in a sustained inhibition of the target17. Btk is required 
for B-cell receptor (BCR) signaling18 but is also critical for mast cell degranulation, acting 
downstream of the high-affinity IgE receptor FcεRI19. Based on preclinical data, blockade of the 
BCR signaling pathway by ibrutinib has two major effects: 1) direct induction of apoptosis and 


9 
 
2) inhibition of cell homing and migration to inflammatory chemokines and subsequent adhesion 
to cellular substrates20,21. Since the Btk protein is expressed in most hematopoietic cells with the 
exception of T cells and natural killer (NK) cells18, a wide range of immunomodulatory effects 
are expected following ibrutinib administration. Recently, ibrutinib has been found to block the 
expansion of Myc-driven insulinomas by inhibiting mast cell degranulation. In particular, 
ibrutinib was shown to trigger collapse of tumor vasculature, thus leading to a dramatic tumor 
regression22. This is consistent with the idea that islet–cell tumorigenesis is causally linked, and 
continuously dependent on, infiltration of mast cells16 and that signals from the 
microenvironment are drivers of disease progression in solid cancers23. In addition, ibrutinib has 
been found to apparently inhibit the proliferation of neoplastic islet-cell, although the 
mechanisms underlying this unexpected therapeutic benefit remain unclear22. 
1.3.1.1 Pharmacodynamics 
Pharmacodynamic assays have been used to demonstrate the on-target effect of ibrutinib. 
Preclinical, in vitro models have shown the selectivity of the drug in the inhibition of Btk, as 
compared to other members of the closely related Tec and Src1/Ab1 family kinase (Table 1-3-1-
1). 
Table 1-3-1-1: Median IC50 Values of Ibrutinib Toward Selected Tec and Src/Ab1 Family 
Kinases  
Kinase(a)  
Median 
IC50 (nM)  
N(b)  
Selectivity 
for BTK(c)  
Kinase  
Median 
IC50 (nM) 
N  
Selectivity 
for Btk 
Btk*  
0.39  
7  
1.0  
PAK1  
3737  
1  
9582  
ErbB4/HE
R4*  
0.64  
2  
1.6  
mTor/FRAP
1  
4253  
1  
10905  
Blk*  
0.94  
2  
2.4  
TRKB  
4472  
1  
11467  
Bmx/Etk*  
1.10  
2  
2.8  
MEK2  
5003  
1  
12828  
Fgr  
2.86  
2  
7.3  
MEKK3  
5133  
1  
13162  
Txk*  
2.87  
1  
7.4  
Fms  
5149  
2  
13203  
Lck  
3.49  
4  
9.0  
TRKA  
5595  
1  
14346  
Yes/YES1  
3.94  
2  
10  
Fer  
5635  
2  
14449  
Tec*  
5.49  
2  
14  
NEK2  
12630  
1  
32385  
Csk  
6.17  
2  
16  
CAMK1a  
18950  
1  
48590  
EGFR*  
7.80  
6  
20  
AKT1  
>20000  
1  
>51282  
Brk  
10.10  
2  
26  
AMPK(A1/
B1/G1)  
>20000  
1  
>51282  
Itk*  
11.70  
3  
30  
Axl  
>20000  
1  
>51282  
Hck  
16.98  
2  
44  
c-Met  
>20000  
1  
>51282  
ErbB2/HE
R2*  
21.57  
2  
55  
Cdk1/cyclin 
B  
>20000  
1  
>51282  
JAK3*  
21.90  
3  
56  
ERK1  
>20000  
1  
>51282  
a Kinases labeled with an asterisk (*) have a cysteine in the active site representing a possible target for covalent binding with 
ibrutinib.  
b N = number of independent assays from which median IC50 values were determined.  
c Selectivity ratios were calculated using non-rounded values.  
Moreover, use of a fluorescent probe assay have shown that a single dose of ibrutinib as low as 
2.5 mg/kg is sufficient to fully occupy BTK in peripheral blood and tumor tissue for 24 hours in 
dogs. 
 


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1.3.1.2 Pharmacokinetics 
 
After oral administration, ibrutinib exhibited rapid absorption and high plasma clearance in 
preclinical species. In both rats and dogs, the oral bioavailability was less than 25%. Ibrutinib 
exposure increased with increasing doses and at dose ≥30 mg/kg was higher in female than in 
male rats. Gender had no apparent effect on oral exposure in dogs. The mean terminal half-life of 
ibrutinib after oral administration was less than 5 hours in rodents and 3 to 6 hours in dogs. In 
vitro binding of ibrutinib to plasma protein was high and comparable in mice, rats, dogs, and 
humans. Ibrutinib was preferentially bound to human serum albumin and less to human α1-acid 
glycoprotein. The drug is metabolized by CYP3A4/5 and biliary excretion is its major route of 
elimination in rats. 
 
1.3.1.3 Toxicology 
The nonclinical safety profile of ibrutinib has been well characterized through the conduct of 
single-dose and repeat-dose toxicity studies of up to 13 weeks in duration, and safety 
pharmacology, genetic toxicity, reproductive and developmental toxicity, immunotoxicity and 
phototoxicity studies.  The primary target organ toxicities were observed in the lymphoid, 
gastrointestinal and skeletal systems. Ibrutinib was not identified as a mutagen or clastogen. In 
reproductive studies ibrutinib at 80 mg/kg/day (approximately 14 times the AUC of ibrutinib 
compared to patients at the dose of 560 mg daily) was associated with increased post-
implantation loss, increased visceral malformations (heart and major vessels) and skeletal 
variations. After immunophenotyping analysis, absolute total B-cell counts were found to be 
decreased following ibrutinib administration in rats. Minimal phototoxicity potential was 
identified after evaluation of UV spectrum, photostability, and whole rat distribution data. 
1.3.2 Ibrutinib clinical experience 
As of 13 December 2013, 24 studies evaluating the safety, efficacy and pharmacokinetics (PK) 
of ibrutinib have been completed or are ongoing. These include 3 dose-finding Phase 1 studies, 5 
studies in healthy volunteers, 7 Phase 2 studies using fixed continuous doses of ibrutinib, 1 Phase 
1b study and 1 Phase 2 study combining ibrutinib with chemotherapy or immunotherapy, 5 
randomized Phase 3 studies with 3 studies testing single-agent ibrutinib and 2 studies testing 
ibrutinib in combination, 1 extension study, and 1 extended-treatment rollover safety study for 
subjects who had participated in previous studies with ibrutinib. Across all studies, malignancies 
under investigation include chronic lymphocytic leukemia, small lymphocytic lymphoma, 
mantle-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, multiple myeloma, 
and Waldenstrom macroglobulinemia. Ibrutinib has never been tested in clinical trials evaluating 
patients with solid tumors. 
1.3.2.1 Pharmacokinetics 
The pharmacokinetics (PK) of ibrutinib has been assessed in subjects with B-cell malignancies 
as well as in healthy subjects. Following oral administration of ibrutinib at doses ranging from 
1.25 to 12.5 mg/kg/day as well as fixed dose levels of 420, 560, and 840 mg/day, exposure to 


11 
 
ibrutinib increased as doses increased with substantial intersubject variability. The mean half life 
(t1/2) of ibrutinib across 3 clinical studies ranged from 4 to 9 hours, with a median time to 
maximum plasma concentration (Tmax) of 2 hours. Administration of 420 mg ibrutinib with a 
high-fat breakfast in subjects with chronic lymphocytic leukemia (CLL) approximately doubled 
the mean systemic exposure compared to intake after overnight fasting with median time to 
Tmax delayed from 2 to 4 hours. Ibrutinib absorption from the GI tract is practically complete, as 
minimal fecal excretion of unchanged ibrutinib in combination with high levels of oxidative 
metabolites (liver and gut metabolism) and a lack of reduction products (gut microflora 
metabolism) was observed. The plasma protein binding of ibrutinib in human plasma is 97.3% 
and distribution to peripheral tissues is extensive.  Ibrutinib is extensively metabolized by 
CYP3A4 to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of Btk, with 
approximately 15 times lower inhibitory potency compared to ibrutinib. The metabolite-to-parent 
AUC ratio ranged from 0.7 to 3.4. Steady-state exposure of ibrutinib and PCI-45227 was less 
than 2-fold of first dose exposure. 
The results of human mass balance study of [14C]-ibrutinib conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally excreted, 
whereas approximately 80% is recovered in feces. Subjects with mild and moderate renal 
insufficiency (creatinine clearance > 30 mL/min) were eligible to enroll in Study PCYC-1102-
CA in which pharmacokinetic (PK) assessments were included. No dose adjustment is needed 
for mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There is 
no data in patients with severe renal impairment or patients on dialysis. The study of ibrutinib in 
hepatic impaired subjects is currently in progress. 
Significant PK interactions were observed in drug-drug interaction studies in healthy subjects 
with ketoconazole and rifampin as strong CYP3A4/5 inhibitor and inducer, respectively. On the 
contrary, in vitro data on CYP inhibition and induction do not suggest a clinically relevant effect 
of ibrutinib or its metabolites on the metabolism of concomitant medications. 
1.3.2.2 Ibrutinib in healthy volunteers 
In healthy subjects ibrutinib up to 560 mg was generally well tolerated. The most common 
treatment-emergent adverse events were of grade 1 in severity, with the exception of reported 
grade 2 headache and rash. Recovery from toxicities was rapid. 
1.3.2.3 Ibrutinib in mantle-cell lymphoma 
A phase 2 study25 investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with 
relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who 
had previously received at least 2 cycles of bortezomib therapy and those who had received less 
than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The 86% of 
patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic 
factors. The most common treatment-related adverse events were mild or moderate diarrhea, 
fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included 


12 
 
neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response 
rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial 
response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With 
an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 
months (95% CI, 15.8 to not reached), the estimated median PFS was 13.9 months (95% CI, 7.0 
to not reached), and the median OS was not reached. The estimated rate of overall survival was 
58% at 18 months. Based on these data, ibrutinib received FDA approval and should be used at 
first relapse in patients with mantle-cell lymphoma26. 
1.3.2.4 Ibrutinib in chronic lymphocytic leukemia 
Ibrutinib has been tested in a phase 1b-2 multicenter study27 in patients with relapsed or 
refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. A total of 85 patients, 
the majority of whom were considered to have high-risk disease, received the drug orally once 
daily; 51 received 420 mg, and 34 received 840 mg. Toxic effects were predominantly grade 1 or 
2 and included transient diarrhea, fatigue, and upper respiratory tract infection. The overall 
response rate was the same in the group that received 420 mg and the group that received 840 mg 
(71%), and an additional 20% and 15% of patients in the respective groups had a partial response 
with lymphocytosis. The response was independent of clinical and genomic risk factors present 
before treatment, including advanced-stage disease, the number of previous therapies, and the 
17p13.1 deletion. At 26 months, the estimated PFS rate was 75% and the rate of OS was 83%. 
More recently, a multicenter, open-label, phase 3 study28 has randomized 391 patients with 
relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma to receive 
daily ibrutinib or the anti-CD20 antibody ofatumumab. At a median follow-up of 9.4 months, 
ibrutinib significantly improved PFS; the median duration was not reached in the ibrutinib group 
(with a rate of PFS of 88% at 6 months), as compared with a median of 8.1 months in the 
ofatumumab group. At 12 months, the OS rate was 90% in the ibrutinib group and 81% in the 
ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than 
in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated 
patients had a partial response with lymphocytosis. Similar effects were observed regardless of 
whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most 
frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the 
ibrutinib group. Consistent with these results, FDA has granted approval for ibrutinib in patients 
with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. 
1.3.2.5 Ibrutinib in other hematological malignancies 
Phase III trials are underway worldwide to evaluate ibrutinib in the treatment of patients with 
diffuse large B-cell lymphoma, and the agent is in phase II development for use in follicular 
lymphoma, multiple myeloma and Waldenstrom macroglobulinemia29. Ibrutinib has been 
investigating as monotherapy or in combination with R-CHOP regimen in patients with diffuse 
large B-cell lymphoma. Preliminary safety data suggest fatigue, diarrhea, nausea, anemia, and 
thrombocytopenia as most commonly occurring treatment-emergent adverse events. In myeloma 


13 
 
patients, the most commonly reported toxicities were nausea, diarrhea, arthralgia, muscle spasms 
and fatigue, anemia, thrombocytopenia, pyrexia and epistaxis. Majority of the adverse events 
were of Grade 1 or 2 in severity. The most commonly reported Grade 3 adverse events were 
hypophosphatemia, syncope, and anemia. 
1.3.3 Summary of Clinical Safety of ibrutinib 
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs >10%   
Most frequently reported 
Grade 3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 
 
For more detailed information refer to the current version of the IB. 
 
1.3.3.2 Cytopenias 
Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. 
1.3.3.3 Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe. Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.2). 
 
1.3.3.4. 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, 
Comment [AT1]: RESPONSE REQUIRED: 
 
Please update Ibrutinib safety language to the 
following per IB v.9. 


14 
 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. See Section 5.3 for guidance 
on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section 5.5 
for guidance on ibrutinib management with surgeries or procedures. 
 
1.3.3.5 Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation. For atrial fibrillation which persists, consider the risks and benefits of ibrutinib 
treatment and follow the protocol dose modification guidelines (see Section 5.2). 
1.3.3.6 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.  
1.3.3.7 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. 
 
1.3.3.8 Infection 
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.  
 
1.3.3.9 Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-
agent ibrutinib or in combination with chemotherapy. Subjects at risk of tumor lysis syndrome 
are those with comorbidities and/or risk factors such as high tumor burden prior to treatment, 
increased uric acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at 
baseline, and pre‐existing kidney abnormalities. 


15 
 
1.4 
Study rationale 
It is becoming increasingly clear that the microenvironment has a crucial role in the progression 
of both hematological and solid tumors. In particular, preclinical data suggests that mast cells are 
recruited within NETs where they remodel the stroma and stimulate angiogenesis, driving 
macroscopic tumor expansion16. Inhibitors of mast cell degranulation have been shown to block 
this process, driving tumor shrinkage, at least in mouse models22. Ibrutinib can affect mast cell 
degranulation, acting downstream the high affinity IgE receptor FcεRI19. Given its favorable 
risk/benefit ratio for investigation in NETs, we plan to test the hypothesis whether ibrutinib can 
cause tumor regression in both carcinoid tumors and pNETs. 
2. Study objectives 
The primary purpose of the study is to determine the objective response rate to ibrutinib therapy 
in patients with advanced (unresectable or metastatic) low to intermediate grade carcinoid tumors 
or pNETs. 
Secondary objectives are: 
 to investigate the progression-free survival (PFS) and overall survival (OS) associated 
with ibrutinib in patients with advanced carcinoid tumors or pNETs; 
 to evaluate the duration of response of carcinoid or pNET patients receiving ibrutinib; 
 to assess changes in tumor markers and changes in quality of life (QOL) in NET patients 
administered with ibrutinib; 
 to determine the safety and tolerability of ibrutinib in this patient population. 
2.1 Selection of doses 
Based on the tolerable side-effect profile of ibrutinib at doses of 560 mg daily in other neoplasms 
and pharmacokinetic data demonstrating therapeutic drug levels at that level (see section 1.3.2), 
the dose of ibrutinib in this study will be 560 mg once daily. If tolerability issues occur, the 
treatment dose may be reduced as described in section 5.2. 
3. Endpoints 
3.1 
Primary endpoints 
1. Overall radiographic response rate (ORR), as defined by RECIST v1.1. 
3.2 
Secondary endpoints 
1. Median PFS and PFS rate at 1 year 
2. Median OS and OS at 1 year 
3. Duration of response 
4. Adverse events (AEs) 


16 
 
5. Changes in neuroendocrine tumor markers (such as chromogranin A or pancreatic 
polypeptide), or hormonal assays (such as urine 5-HIAA, gastrin, glucagon, vasoactive 
intestinal peptide, etc) if elevated at baseline (> upper limit of normal, ULN); 
6. Changes in quality of life (as measured by EORTC questionnaires EORTC QLQ-C30 and 
QLQ GI.NET21). 
3.3 
Exploratory endpoint 
1. To determine whether the presence and activation of mast cells in the tumor tissue sample 
predicts for response; 
2. To determine whether changes in serum Tryptase-β2 correlate with response. 
4. Investigational plan 
4.1 
Overall study design 
This is a prospective phase II open-label trial, stratifying patients equally into two cohorts 
consisting of carcinoid tumors and pNETs.  
4.2 
Treatment 
The investigational drug used in this study is ibrutinib 560 mg.  Ibrutinib will be administered 
orally once daily and each cycle will be defined as 4 weeks duration. Study treatment should 
begin within 14 days following enrollment into the study and continue until disease progression, 
unacceptable toxicity, or withdrawal of consent.  Safety and efficacy will be assessed throughout 
the treatment period. 
4.3 
Study population 
The study population will consist of adult patients with histologically confirmed low to 
intermediate grade NETs of the GI tract, lungs and unknown primary (carcinoid tumors) or 
pNETs. All patients must be confirmed to have advanced disease. The study will enroll up to 51 
patients in two cohorts (30 carcinoid and 21 pNET patients). 
4.4 
Inclusion/exclusion criteria 
The investigator or his/her designee must ensure that all patients who are offered enrollment in 
the study meet all of the following inclusion and exclusion criteria: 
4.4.1 Inclusion criteria 
1. Locally unresectable or metastatic carcinoid or pNET; 
2. Measureable disease by RECIST criteria; 
3. Tumors must be histologically or cytologically proven and considered low or intermediate 
grade. Patients with high grade neuroendocrine carcinomas or small cell carcinomas are 
excluded from the study; 
4. Evidence of progressive disease within 12 months of study entry; 
5. Allowed prior therapies include: 


17 
 
a) Surgery (major surgery at least more than four weeks prior to baseline assessment); 
b) Locoregional 
therapy 
such 
as: 
chemoembolization, 
radio-embolization, 
radiofrequency ablation, radiotherapy as long as there is progressive measurable 
disease outside the area of locoregional therapy or there is progression in the 
previously treated areas; 
c) Any number of previous lines of systemic therapy.  Last treatment before enrollment 
must have occurred more than 4 weeks for chemotherapy, 6 weeks for antibodies or 
more than 5 half lives of prior TKIs or small moleculs; 
6. Prior or concurrent therapy with somatostatin analogs is permitted for patients with secretory 
NET; 
7. All patients with gastroenteropancreatic NETs must have progressed on (or are intolerant of) 
prior somatostatin analog; 
8. Patients with pancreatic NETs must have have progressed on (or are intolerant of) either 
everolimus or sunitinib; 
9. Age ≥ 18 years; 
10. ECOG performance status of 0-2; 
11. Life expectancy 12 weeks or more; 
12. Adequate bone marrow function as shown by: absolute neutrophil count ≥ 1,000/mm3, 
Platelets ≥ 100,000/mm3, Hb > 10 g/dl; 
13. Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN, and serum transaminases 
activity ≤ 2.5 x ULN, with the exception of serum transaminases (< 3 x ULN) if the patient 
has liver metastases; 
14. Adequate renal function as shown by serum creatinine ≤ 2 mg/dl; 
15. Women of childbearing potential must have a negative serum pregnancy test within 7 days of 
the administration of the first study treatment. Women must not be lactating. Both men and 
women of childbearing potential must be advised of the importance of using effective birth 
control measures during the course of the study. Childbearing potential for women and men 
is defined in section 4.4.3; 
16. Signed informed consent to participate in the study must be obtained from patients after they 
have been fully informed of the nature and potential risks by the investigator (or his/her 
designee) with the aid of written information. 
4.4.2 Exclusion criteria 
1. High grade NET or small cell neuroendocrine carcinoma; 
2. Clinically apparent central nervous system metastases or carcinomatous meningitis; 
3. Known positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or 
hepatitis C virus (HCV); 
4. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study 
drug; 
5. Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, 
or any class III or IV cardiac disease as defined by the NYHA functional classification; 
6. Requirement for anticoagulation with warfarin or similar vitamin K antagonists.  


18 
 
7. Requirement for treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor. (See 
Appendix A) 
8. Prior antitumor therapy within 2 weeks of enrollment (with the exception of somatostatin 
analogs); 
9. No other active malignancy within 3 years of enrolment except adequately treated basal cell 
or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer 
from which the patient is currently in complete remission, or any other cancer from which the 
patient has been disease free for at least three years; 
10. Any medical condition or organ system dysfunction which, in the investigator’s opinion, 
could compromise the patient’s safety, interfere with the absorption or metabolism of 
ibrutinib; 
11. Known hypersensitivity to ibrutinib or any component of the ibrutinib formulation; 
12. History of noncompliance to medical regimens or unwillingness to comply with the protocol. 
13. Currently active, clinically significant hepatic impairment Child-Pugh class B or C according 
to the Child Pugh classification (see Appendix D) 
4.4.3 Definition of childbearing potential 
All women are considered of childbearing potential, unless they meet at least one of the 
following criteria: 
 
a) Females who are menopausal, defined as follows: i) Females who are younger than 55 
years old will be considered menopausal if they satisfy all the following three requirements 
during screening: 1) they are in amenorrhea, defined as absence of menstruation for the previous 
12 months; 2) they have a negative urine pregnancy test; and 3) they have a serum FSH level 
within the laboratory reference range for postmenopausal females; ii) Females who are older 
than 55 years old: they will be considered menopausal if they are in amenorrhea, defined as 
absence of menstruation for the previous 12 months before screening.  
 
b) Females who have a documented hysterectomy and/or bilateral oophorectomy and/or 
tubal ligations. 
  
All men are considered of childbearing potential, unless they meet at least one of the following 
criteria: 
 
a) Males who have a documented vasectomy more than 6 months prior to the 
administration of the first study treatment. 
 
b) Female partner/partners who are menopausal (as previously defined) and/or who have a 
documented hysterectomy and/or bilateral oophorectomy and/or tubal ligations. 
 
5. Study Medication 
5.1 
Study drug: ibrutinib 
The investigational drug used in this study is ibrutinib, available as 140 mg capsules. The 
inactive ingredients of ibrutinib include:  microcrystalline cellulose, croscarmellose sodium, 
sodium lauryl sulfate and magnesium stearate. 
Comment [AT2]: RESPONSE REQUIRED: 
 
Please include the following exclusion criteria 
regarding hepatotoxicity. 


19 
 
Pharmacyclics will supply ibrutinib as long as the patient remains on study, shows continuous 
benefit from treatment, and there are no safety concerns.  Ibrutinib  should be stored  at room 
temperature (20°C to 25°C, equivalent to 68°F to 77°F). Excursions are permitted between 15°C 
and 30°C (59°F to 86°F). 
The starting dose is 560 mg (four 140 mg capsules) taken once daily orally. Doses should be 
taken approximately the same time each day, without scheduled breaks. Patients who vomit 
anytime after taking a dose should not “make it up” with extra doses, but instead resume 
subsequent doses as planned.  Any missed dose may be taken as soon as possible on the same 
day with a return to the normal schedule the following day.  If doses are missed or vomited, this 
must be indicated in the source documents and CRFs.  A treatment cycle will be defined as 4 
weeks duration. To monitor the correct self-administration of ibrutinib, enrolled patients will be 
provided with a diary. 
Study treatment should begin within 14 days following enrollment onto the study. Patients 
should be requested to bring their unused medication to the clinic each visit.  Compliance should 
be verified by the investigator's staff through counting the number of capsules consumed 
between visits.  The investigator (or his/her designee) will document dosage administration and 
all dose changes during the study in the CRF.  The dose, amount dispensed, amount received, 
and amount remaining unused must be recorded. 
Patients will be assessed for response after every 3 cycles (12 weeks) of therapy. Patients with 
evidence of stable disease or response to therapy as defined by RECIST v1.1 will continue 
protocol therapy. The dose of ibrutinib will be adjusted for toxicity as outlined below. Patients 
with unacceptable toxicity or progressive disease will discontinue protocol therapy. 
5.2 
Dose Modification 
Ibrutinib should be held or reduced in dose for toxicity or for concomitant use of CYP3A 
inhibitors (see Appendix A), as described in the sections below. Ibrutinib dosing adjustments are 
to be made according to the greatest degree of toxicity observed. Doses of ibrutinib which have 
been reduced for toxicity may not be re-escalated. All interruptions or changes to study drug 
administration must be recorded. If any patient discontinues study treatment or post-treatment 
observation, then the reason will be recorded. 
Patients experiencing drug-related toxicities that are grade 1 or 2 according to CTCAE criteria 
should continue ibrutinib without dose modification. However the investigator may reduce the 
dose by one level if a grade 2 toxicity persists and significantly affects patient quality of life. If a 
patient experiences a CTCAE grade 3 or higher non-hematological toxicity, a grade 3 or higher 
neutropenia with infection or fever, or a grade 4 hematological event that is considered drug-
related, ibrutinib should be held until resolution of toxicity to ≤ grade 1. Then the drug should be 
reinitiated at the starting dose. If the toxicity reoccurs, the dose should be reduced by one capsule 
(140 mg per day). A second reduction of dose by 140 mg may be considered as needed as per 
Table 5-2. If a patient experiences these drug-related toxicities despite two dose reductions, 
ibrutinib should be discontinued and the patient should be taken off the study. Patients should 
also be removed from study if off treatment for >3 weeks.  
Recommended dose modifications for these toxicities are described below: 
Table 5-2:  Recommended dose modifications for ibrutinib 


20 
 
Toxicity occurrence 
Dispensed As 
First 
Restart at 560 mg daily 
Second 
Restart at 420 mg daily 
Third 
Restart at 280 mg daily 
Fourth 
Discontinue Ibrutinib 
 
5.2.1 Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of screening (Child-Pugh class B or C) are excluded from study 
participation. For subjects who develop mild liver impairment while on study (Child-Pugh class 
A), the recommended dose reduction for ibrutinib is to a level of 280 mg daily (two capsules). 
For subjects who develop moderate to severe liver impairment while on study (Child-Pugh class 
B), the recommended dose reduction is to a level of 140 mg daily (one capsule). Subjects who 
develop severe hepatic impairment (Child-Pugh class C) must hold study drug until resolved to 
moderate impairment (Child-Pugh class B) or better. Subjects will be monitored for signs of 
toxicity and follow dose modification guidance as needed (Refer to Appendix D). 
5.3 
Concomitant therapy 
 All patients should be maintained on the same medications throughout the study period, 
as medically feasible; 
 The investigator should instruct the patient to notify the study staff about any new 
medications he/she takes after the start of the study drug. All medications (other than 
study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient starts treatment with study drug must be 
recorded; 
 Administration of pegfilgrastim or filgrastim following initiation of protocol therapy is at 
invesigator’s discretion for all patients; 
 Administration of erythropoietin or darbopoietin is allowed; 
 Other concurrent investigational drugs of any type are not allowed in the trial; 
 Other concurrent anticancer agents (with the exception of somatostatin analogs) are not 
allowed in the trial; 
 Patients must be instructed not to take any additional medications (including herbal 
supplements and over-the-counter products) during the trial without prior consultation 
with the investigator. All medications taken within 30 days of screening should be 
recorded. If concomitant therapy must be added or changed, the reason and name of the 
drug/therapy should be recorded; 
 In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient are allowed, including drugs given prophylactically (e.g. antiemetics or 
steroids), with the following exceptions: 
 CYP3A Inhibitors/Inducers 
 
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. 
Comment [AT3]: RESPONSE REQUIRED: 
 
Please include the following required dose 
modification language on hepatic impairment. 


21 
 
Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) should be avoided 
 If a strong CYP3A inhibitor (see Appendix A) must be used, ibrutinib will be 
reduced to 140 mg or withheldfor the duration of inhibitor use.. Subjects will be 
monitored more closely for signs of ibrutinib toxicity (at the investigator’s 
discretion). If a moderate CYP3A inhibitor (see Appendix A) must be used, 
ibrutinib will be reduced to 140 mg (for 840 mg/day dose, reduce to 280mg) for 
the duration of the inhibitor use. No dose adjustment is required in combination 
with mild inhibitors. 
 Grapefruit and Seville oranges should be avoided during ibrutinib treatment, as 
these contain moderate inhibitors of CYP3A (see Appendix A) 
 Co-administration of ibrutinib with strong CYP3A inducer, rifampin, in healthy 
subjects decrease ibrutinib plasma concentrations by approximately 10-fold. 
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A 
induction. 
  
 A list of common CYP3A inhibitors and inducers is provided in Appendix A.  A 
comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ This website is continually 
revised and should be checked frequently for updates. 
 Anti-platelet Agents and Anticoagulants:  
 Warfarin or vitamin K antagonists should not be administered concomitantly with 
ibrutinib. Supplements such as fish oil and vitamin E preparations should be 
avoided. Use ibrutinib with caution in subjects requiring other anticoagulants or 
medications that inhibit platelet function. Subjects with congenital bleeding 
diathesis have not been studied. For guidance on ibrutinib and the use of 
anticoagulants during procedures/surgeries see Section 5.5. 
 Patients who need to be on anticoagulant therapy during treatment with ibrutinib 
should be treated with low molecular weight heparin as the preferred therapy. 
Patients who are on full dose anticoagulation therapy while being treated with 
ibrutinib and who experience concurrent grade 3 or 4 thrombocytopenia/bleeding 
despite single ibrutinib dose reduction will permanently discontinue ibrutinib 
treatment. 
 Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial 
fibrillation), consider the risks and benefits of continuing ibrutinib treatment. If 
therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should 
be held and not be restarted until the subject is clinically stable and has no signs 
of bleeding. Subjects should be observed closely for signs and symptoms of 
bleeding. No dose reduction is required when study drug is restarted. 
5.3.1 Drugs That May Have Their Plasma Concentrations Altered by 
Ibrutinib 


22 
 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL). Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose. There is no clinical data available; therefore, co-
administration of narrow therapeutic index P-gp substrates (eg, digoxin) with ibrutinib may 
increase their blood concentration and should be used with caution and monitored closely for 
toxicity.  
5.3.1.1 QT Prolonging Agents  
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered. 
5.3.1.2 Antiplatelet Agents and Anticoagulants  
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied. Ibrutinib should be held at 
least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of 
bleeding (see Section 5.5).  
 
5.4 
Interruption or Discontinuation of Treatment 
Patients may be removed from study for the following reasons: 
 
Documented disease progression or symptomatic tumor progression. In the case of 
symptomatic tumor progression, all efforts should be made to document disease status 
radiologically prior to removal from study; 
 
Occurrence of unacceptable toxicity (see table 5-2 regarding dose modifications for 
toxicity). Patients removed from treatment for intolerable toxicity should still be 
followed with regular tumor assessments until disease progression or start of a new 
treatment; 
 
Patient has been off treatment for >3 weeks; 
 
The patient chooses to terminate participation in the study; 
 
At the discretion of the investigator; 
 
If, at any time, the constraints of this protocol are detrimental to the patient’s health 
and/or the patient no longer wishes to continue protocol therapy, protocol therapy shall 
be discontinued. In this event the study chairs should be notified, the reasons for 
discontinuation should be documented, and the patient should be followed as appropriate 
per study. 
5.5 Guidelines for Ibrutinib Management with Surgeries or Procedure  
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for patients who 
require surgical intervention or an invasive procedure while receiving ibrutinib:  


23 
 
5.5.1. Minor Surgical Procedures  
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should not be 
restarted for at least 3 days after the procedure.  
 
5.5.2. Major Surgical Procedures  
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention and should be held at least 7 days after the procedure 
and restarted at the discretion of the investigator when the surgical site is reasonably healed 
without serosanguineous drainage or the need for drainage tubes.  
5.5.3. Emergency Procedures  
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, for at least 7 days after the urgent surgical procedure. 
6. Visit schedule and assessments 
6.1 
Pretreatment Evaluation 
Baseline tumor and patient characteristics including: 
 
 Patient demographics: age, gender and race  
 Medical history; 
 Medications; 
 ECOG performance status; 
 Type of neuroendocrine tumor: primary site (if known) vs. unknown; 
 Differentiation or grade (if available); 
 Known sites of metastases; 
 Presence or absence of hormonal syndrome (carcinoid syndrome, gastrinoma syndrome, 
insulinoma syndrome, etc.); 
 Presence or absence of a pathologically elevated hormone or biomarker; 
 EORTC QLQ C-30 and EORTC QLQ GI-NET21 questionnaires. 
 
Tests to be performed within 28 ±2 days prior to initiation of therapy (if day 28 falls on a 
weekend or holiday the deadline may be extended to the next working day): 
 
 Radiologic assessment of tumor burden by CT scan or MRI; In all cases, imaging studies 
should encompass the abdomen and any other known sites of measurable disease. For 
small bowel NETs, imaging of the abdomen and pelvis is recommended. For pancreatic 
NETs, abdominal imaging is sufficient if there are no known extra abdominal sites.  For 
lung NETs, imaging of the thorax and abdomen is recommended.    
 Assessment of secretory proteins. All patients will undergo an initial assessment of 
chromogranin A. Patients with suspected serotonin-producing tumors (and all patients 
with midgut carcinoid tumors) will have a 24 hour urine 5-HIAA measured at baseline.  
Other possible neuroendocrine tumor markers/hormones (e.g. pancreatic polypeptide, 


24 
 
gastrin, glucagon, etc.) may be collected at the discretion of the investigator based on 
clinical symptoms and tumor location. 
 
Tests to be performed within 14 ±2 days prior to initiation of therapy (if day 14 falls on a 
weekend or holiday the deadline may be extended to the next working day): 
 
 History and physical evaluation including height, weight, vital signs and performance 
status; 
 Baseline hematological and biochemical profiles including CBC with differential and 
comprehensive metabolic panel (fasting glucose, sodium, potassium, calcium, chloride, 
bicarbonate, creatinine, blood urea nitrogen, albumin, SGOT (AST) SGPT (ALT) total 
bilirubin and alkaline phosphatase); 
 Serum pregnancy test for women of childbearing potential; 
 Correlative laboratory studies with the potential to correlate with response to the 
treatment (measurement of serum Tryptase-β2). 
6.2 
Evaluations During Treatment 
 
 
Beginning of every cycle (defined as 28 ±2 days): 
 Physical examination; 
 Toxicity assessment; 
 Vital signs; 
 Weight; 
 ECOG performance status; 
 CBC with differential; 
 Fasting comprehensive metabolic panel; 
 Assessment of adverse events. 
 
Data to be obtained every 3 cycles ±1 week of treatment until disease progression, unacceptable 
toxicity or withdrawal of consent: 
 Radiologic assessment of tumor burden by CT scan or MRI; 
 Assessment of chromogranin A and/or other tumor markers or hormones if elevated at 
baseline (see section 6.1); 
 EORTC QLQ C-30 and EORTC QLQ GI-NET21 questionnaires; 
 Correlative laboratory studies (see section 6.1). 
 
Patients who have an ongoing grade 4 or serious adverse event at the time of discontinuation 
from study drug treatment will continue to be followed at no less than monthly intervals, until 
resolution of toxicity to less than grade 2. 
6.3 
Instructions for processing correlative laboratory studies 
 
Correlative laboratory studies will include the assessment of blood- and tissue-based biomarkers 
with the potential to correlate with response to treatment. 


25 
 
6.3.1 Blood-based biomarkers 
Blood will be collected every three months. Serum measurement of Tryptase-β2 will be 
performed by ELISA in the Translational Research Core of the Moffitt Cancer Center. 
6.3.2 Tissue-based biomarkers: 
If available, archival tissue containing a tumor block (preferred) or 10 unstained slides (3-5 
micron thick) from patient’s primary or metastatic neuroendocrine tumor should be sent to 
Moffitt Cancer Center for correlative immunohistochemical studies. Specimens should be placed 
in a secure, airtight container, labeled with the patient name and study number. 
Site should contact Moffitt Cancer Center at (813) 745-3275 with expected delivery date. 
 
Shipping address: 
Attention Dr. Domenico Coppola 
Anatomic Pathology Dept. 
H. Lee Moffitt Cancer Center 
12902 Magnolia Ave 
Tampa, FL 33612  
Immunohistochemistry (IHC) will be used to evaluate the expression of c-kit, tryptase and 
chymase as markers for mast cell presence and activation, respectively. Sections of 3-4 microns 
in thickness will be cut from the selected formalin-fixed paraffin embedded tissue and subjected 
to IHC staining protocol using the Dakocytomation Autostainer (DakoCytomation, Carpitenria, 
Calif). Microwave antigen retrieval with IHC Select EDTA buffer, pH 7.5, will be utilized.  
Primary antibodies with cross-reactivity against the human subtypes of the above mentioned 
targets will be diluted and incubated for 60 minutes at room temperature. Using a 
semiquantitative scoring system, the intensity of IHC staining for c-kit, chymase and tryptase 
will be scored as either 0 (negative), 1+ (mild positive staining), 2+ (moderate positive) and 3+ 
(strong positive staining). The correlation between staining patterns and clinical outcomes 
(response rate or PFS) will be analyzed in a descriptive fashion. 
 
6.4 
Evaluation schema 
Table 6-5 lists all of the assessments and indicates the visits at which they are to be performed 
with an “X”. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
Table 6-5 
Visit evaluation schedule 
Evaluation 
Screening/ 
Baselinea 
Each Cycle (day 1 
±2) 
Every 3 Cycles 
±1 week 
(until disease 
progression, 
unacceptable 
toxicity or 
withdrawal of 
consent) 
Endb 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Relevant medical 
X 
X 
 
X 


26 
 
history/ current medical 
conditions 
Diagnosis and extent of 
cancer  
X 
 
 
 
Physical exam  
X 
X 
 
X 
Vital signs  
X 
X 
 
X 
ECGc  
X 
 
 
 
ECOG Performace 
Status 
X 
X 
 
X 
CBC with differentiald 
X 
X 
 
X 
Glycosylated 
hemoglobin 
X 
 
 
 
Fasting Comprehensive 
metabolic panele 
X 
X 
 
X 
Pregnancy test and 
review of contraceptionf 
X 
 
 
 
Secretory hormonesg 
and serum 
chromogranin A 
X 
 
X 
X 
Radiologic assessment 
of tumor burdenh 
X 
 
X 
X 
Adverse eventsi 
X 
X 
 
X 
Concomitant 
medicationsj 
X 
X 
 
X 
EORTC QLQ C-30 and 
EORTC QLQ GI-NET21 
questionnaires 
X 
 
X 
 
Correlative laboratory 
studiesk 
X 
 
X 
 
 
a Screening includes review of: demography/informed consent, inclusion/exclusion criteria, 
relevant medical history/concomitant medications, diagnosis and extent of cancer. 
 
b Patients who interrupt or permanently discontinue ibrutinib due to an adverse event or 
abnormal laboratory value must be followed at no less than monthly intervals, until resolution of 
toxicity to less than grade 2. These patients will be censored, and tumor assessment will be 
performed off trial at treating physician’s discretion.. Patients will be followed for OS each 12 
months using their charts or the Social Security Death Index. 
 
c ECG should be done at any time when clinically indicated. 
 
d Complete blood count must include: hemoglobin, hematocrit, platelets, total while blood cell 
count and differential. 
  
e Comprehensive metabolic panel should include fasting glucose, sodium, potassium, calcium, 
chloride, bicarbonate, creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), 
SGPT (ALT), total bilirubin and alkaline phosphatase.  
 


27 
 
f For women of child-bearing potential: women of childbearing potential must have a negative 
serum preganancy test within 14 days of enrollment. Acceptable contraception must be used 
while on study and for at least 60 days after last dose of ibrutinib. 
 
g If patients present with hormonally active tumor, secretory hormone levels corresponding to the 
syndrome (e.g. urine 5-HIAA, gastrin, glucagon, insulin, etc.) should be measured at baseline, at 
each restaging cycle and at the end of study treatment. 
 
h Baseline radiologic tests (CT or MRI with iv contrast) should include all known sites of 
metastatic disease. For most midgut carcinoid tumors, a CT or MRI scan of the abdomen and 
pelvis is indicated. For pancreatic neuroendocrine tumors, a CT or MRI scan of the abdomen 
may be sufficient. Radiological scans documenting target lesions should be repeated every 3 
cycles (12 weeks). The same type of scan should be used at each evaluation. 
 
i See section 9.1 for definitions of adverse events. 
 
j All concomitant medications, including over the counter drugs, should be documented each 
visit. 
 
k Correlative laboratory studies will include measurement of serum Tryptase β2. 
7. Outcome Measures 
 
The primary efficacy endpoint is objective response rate as determined by radiology review. 
7.1 
RECIST Criteria for response 
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guidelines30 will be employed 
in this study. For the purposes of this study, measurable disease is defined as the presence of at 
least one measurable lesion. Measurable lesions must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size 
of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have 
slice thickness >5 mm, the minimum size should be twice the slice thickness). 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 20 mm by chest X-ray. 
 
To be considered pathologically enlarged and measurable, a lymph node must be =15 mm in 
short axis when assessed by CT scan (CT scan slice thickness is recommended to be no greater 
than 5 mm). At baseline and in follow- up, only the short axis will be measured and followed. 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable if the soft tissue component meets the definition of measurability described above. 
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable 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. 


28 
 
 
Non-measurable lesions: all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 to <15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.  Blastic bone lesions are non-measurable. 
Lesions with prior local treatment, such as those situated in a previously irradiated area or in an 
area subjected to other loco-regional therapy, are not considered measurable unless there has 
been demonstrated progression (by RECIST 1.1) in the lesion. 
 
Target lesions: all measurable lesions up to a maximum of two lesions per organ and  five lesions 
in total, representative of all involved organs, should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repetitive measurements 
(either by imaging techniques or clinically). 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.  The baseline sum diameters will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease. If lymph 
nodes are to be included in the sum, only the short axis will contribute. 
 
Non-target lesions: All lesions (or sites of disease) not identified as target lesions, including 
pathological lymph nodes and all non-measurable lesions, should be identified as non-target 
lesions and be recorded at baseline. Measurements of these lesions are not required and they 
should be followed as ‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’. 
 
 
 
7.1.1  Evaluation of target lesions 
Complete response (CR): complete disappearance of all target lesions, confirmed by repeat 
assessments at no less than 4 weeks after the criteria for response are first met. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm 
 
Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum longest diameter. This must be confirmed by repeat assessment at no 
less than 4 weeks after the criteria for response are first met. 
 
Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this may include the baseline sum). The sum must also 
demonstrate an absolute increase of at least 5 mm. 
 
Stable Disease (SD): neither sufficient decrease to qualify for partial response nor sufficient 
increase to qualify for progressive disease. 
7.1.2 Special notes on the assessment of target lesions 
• Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded even if the nodes regress to below 10 mm on study. When lymph nodes are included as 


29 
 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met 
since a normal lymph node is defined as having a short axis of <10 mm. 
 
• Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small. However, sometimes lesions or lymph nodes become so faint 
on a CT scan that the radiologist may not feel comfortable assigning an exact measure and may 
report them as being ‘too small to measure’, in which case a default value of 5 mm should be 
assigned. 
 
• Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 
7.1.3 Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker levels. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR / Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker levels above normal limits. 
 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
 
• When patient has measurable disease. To achieve ‘unequivocal progression’ on the basis of the 
non-target disease, there must be an overall level of substantial worsening in nontarget disease 
such that, even in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of one or more 
non-target lesions is usually not sufficient to qualify for unequivocal progression status. 
 
• When patient has only non-measurable disease. There is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. Because 
worsening in non-target disease cannot be easily quantified, a useful test that can be applied is to 
consider if the increase in overall disease burden based on change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease. Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or an increase 
in lymphangitic disease from localized to widespread. 
 
7.1.4 New lesions 
The appearance of new malignant lesions denotes disease progression. 
 
• The finding of a new lesion should be unequivocal (i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something other 
than tumor, especially when the patient’s baseline lesions show partial or complete response). 


30 
 
 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
 
• A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and disease progression. 
 
Cytology and Histology: if the measurable disease is restricted to a solitary lesion, its neoplastic 
nature should ideally be confirmed by cytology or histology. These techniques can be used to 
differentiate between PR and CR in rare cases. 
 
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, stable disease, and progressive disease. 
 
7.1.5 Evaluation of response 
Evaluation of Best Overall Response: the best overall 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).  In general, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria. 
Table 7-1-5 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
Table 7-1-5-1 
Evaluation of best overall response in patients with measurable disease 
 
Target Lesions 
Non-target Lesions New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Inevaluable 
No 
PR 
PR 
Non-PD/or not all 
evaluated  
No 
PR 
SD 
Non-PD/or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 


31 
 
Any 
Any 
Yes 
PD 
 
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. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status. 
 
When patients have non-measurable (therefore non-target) disease only, Table 7-1-5-2 is to be 
used. 
 
Table 7-1-5-2 Evaluation of best overall response in patients with measurable disease 
 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
 
Inevaluable designation: When no imaging/measurement is done at all at a particular time point, 
the patient is not evaluable at that time point. If only a subset of lesion measurements are made at 
an assessment, usually the case is also considered not evaluable at that time point, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) would 
not change the assigned time point response. This would most likely happen in the case of PD. 
7.2 
Guidelines for Evaluation of Measurable Disease 
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. CT is the best currently available 
and reproducible method to measure lesions selected for response assessment. MRI is also 
acceptable in certain situations (e.g., for body scans but not for lung). Lesions on a chest X-ray 
may be considered measurable lesions if they are clearly defined and surrounded by aerated lung. 
However, CT is preferable. Ultrasound (US) should not be used to measure tumor lesions. 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm in 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.   Tumor 
markers alone cannot be used to assess response. If markers are initially above the upper normal 


32 
 
limit, they must normalize for a patient to be considered in complete response. Cytology and 
histology can be used in rare cases (e.g., for evaluation of residual masses to differentiate 
between Partial Response and Complete Response or evaluation of new or enlarging effusions to 
differentiate between Progressive Disease and Response/Stable Disease). Use of endoscopy and 
laparoscopy is not advised. However, they can be used to confirm complete pathological 
response. 
. 
7.3 
Confirmation Measurement/Duration of Response 
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed no less than 4 weeks after the criteria for 
response are first met. In the case of SD, follow-up measurements must have met the SD criteria 
at least once after study entry at a minimum interval of 6 weeks. Progression of disease should be 
verified in cases where progression is equivocal. If repeat scans confirm PD, then progression 
should be declared using the date of the initial scan. If repeat scans do not confirm PD, then the 
subject is considered not to have progressive disease per RECIST 1.1. 
 
Duration of Overall Response: The duration of overall response is measured from the time 
measurement criteria are met for CR/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 complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent 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. 
 
Progression Free Survival (PFS): PFS is defined as the time from the date of first study treatment 
to the date of the first documented disease progression or death due to any cause. If a patient has 
not progressed or died at the date of the analysis cut-off or when he/she receives any further anti-
cancer therapy, PFS is censored at the time of the last tumor assessment before the cut-off or the 
anti-cancer therapy date. 
 
Time to Treatment Failure: Time from administration of the initial dose of ibrutinib until study 
discontinuation for any reason (e.g. disease progression, toxicity, death, withdrawal of consent). 
 
Biochemical marker response will be defined as  50% reduction in tumor marker from baseline. 
 
8. Statistical Considerations 
 
8.1 
Sample size 
 
51 patients (30 patients with carcinoid and 21 patients with pNET). 
 


33 
 
8.2 
Endpoints to be followed 
 
Efficacy Endpoints 
 Tumor response rate using RECIST (Primary endpoint); 
 OS, determined from the time of drug administration to death from any cause (Secondary 
endpoint); 
 PFS, determined as the time from administration of the initial dose of ibrutinib until 
objective tumor progression using RECIST, or death (Secondary endpoint); 
 Duration of response, defined as time from first observation of an objective response 
which is subsequently confirmed, to first disease progression or death due to any cause 
(Secondary endpoint); 
 Changes in health-related quality of life, as assessed by EORTC questionnaires EORTC 
QLQ-C30 and QLQ GI.NET21 (see section 11). 
 
Safety Endpoint  
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry parameters and 
regular physical examinations. Adverse events will be evaluated continuously throughout the 
study. Safety and tolerability will be assessed according to the NIH/NCI Common Terminology 
Criteria 
for 
Adverse 
Events 
version 
4 
(CTCAE 
v4) 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All adverse events 
will be documented on the adverse event CRF. 
 
Exploratory Analyses (refer to Section 6.3) 
As part of this study, we will explore the correlation between early biochemical response and 
response rates or PFS. Early biochemical responders will be defined as patients with elevated 
chromogranin A (CgA) who experience a major reduction (>50%) or normalization of their CgA 
between their baseline (pretreatment) measurement and their follow-up assessment 3 months 
later.   
We also plan to undertake an exploratory analysis of blood- and tissue-based markers that may 
correlate with the clinical outcomes observed in the study. Exploratory markers will include the 
measurement of serum Tryptase-β2 and the determination of the presence and activation of mast 
cells in the tumor tissue samples. 
Archival pathology specimens will be reviewed at the study institution (Moffitt Cancer Center) 
for determination of mitotic rate (number of mitoses per 10 high-powered fields) and Ki-67 
index. 
This study is not sufficiently powered to establish definitive outcome for the correlative 
endpoints. These results will be considered hypothesis generating and any comparison with a 
significant alpha <0.05 will be deemed of sufficient interest to warrant further evaluation. 
 
8.3 
Sample-size Calculation 
This will be a standard, phase II study, in which two cohorts of patients (carcinoid and pNET) 
consisting of 30 patients with carcinoid tumors and 21 patients with pNET each will be enrolled. 


34 
 
We have designed the study to test the null hypothesis that ibrutinib has a response rate of 5% or 
less in this disease. The sample size calculation has been based on the assumption that a true 
response of greater than 18% (comparable with that seen with agents such as sunitinib in pNET13 
or bevacizumab in carcinoid tumors31) would generate interest in a larger randomized study. 
Taking into account both study feasibility given these relatively rare tumor and the relatively 
small difference in H1 and H0, with 30 patients in the carcinoid cohort we will be able to test the 
hypothesis that the true response is 18% versus 5% with a power of 80% and a type 1 error of 
6%, while with 21 patients in the pNET cohort we will be able to test the hypothesis that the true 
response is 20% versus 5% with a power of 80% and a type 1 error of 8%. Patients will be 
accrued to the protocol according to a Simon’s two-stage minimax design. In the carcinoid 
cohort, 15 subjects will be enrolled into stage-1. If 1 or more response is observed, then another 
15 subjects will be enrolled into stage-2. At the completion of the study, if 4 or more responses 
out of N=30 are observed, significance at 6% is reached. Under this design, and if the true 
response rate is ≥18%, then the probability of observing ≥1 response in stage-1 is ≥95%. In the 
pNET cohort, 12 subjects will be enrolled into stage-1. If 1 or more response is observed, 
another 9 subjects will be enrolled into stage-2. At the completion of the study, if 3 or more 
responses out of N=21 are observed, significance at 8% is reached. Under this model, and if the 
true response rate is ≥20%, the probability of observing ≥1 response in stage-1 is 93%. In both 
cohorts, at least 1 patient must respond in the first stage to proceed to the second stage. At any 
point when it is realized that this cannot happen, the study will be stopped in the relative cohort, 
where the therapy will be considered ineffective. 
Kaplan-Meier survival analysis will be performed to evaluate OS, PFS and duration of response. 
8.4 
Replacement of Dropouts 
Patients who enroll but do not receive the initial dose of ibrutinib will be considered dropouts 
and may be replaced.  Additionally, patients who drop out before the first scheduled follow-up 
scan (e.g. completion of the first four cycles of therapy) will be replaced, unless patients drop out 
due to dose-limiting toxicity or progressive disease. Assuming a 10% drop-out rate, 56 patients 
will need to be enrolled to reach 51 evaluable patients. 
 
9.  Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry parameters, and 
regular physical examinations. These assessments should be performed within ±2 days of the 
scheduled day of assessment except for adverse events that will be evaluated continuously 
through the study. Safety and tolerability will be assessed according to the NIH/NCI CTC 
version 4.0. Please refer to: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
9.1 
Adverse events 
Information about all clinically significant adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, laboratory test 
or other means, will be collected and recorded and followed as appropriate. An adverse event is 
the appearance or worsening of any undesirable sign, symptom, or medical condition occurring 


35 
 
after starting the study drug even if the event is not considered to be related to study drug. 
Medical conditions/diseases present before starting study drug are only considered adverse 
events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. Clinically significant laboratory results are those requiring a 
change in the patient’s treatment, further diagnostic testing or specific clinical intervention (i.e., 
treatment delays or dose modifications, etc). The occurrence of adverse events should be sought 
by non-directive questioning of the patient at each visit during the study. Adverse events also 
may be detected when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test, or other assessments. As far as possible, each adverse 
event should be evaluated to determine: 
 the severity grade (mild, moderate, severe) or (grade 1-4) 
 its relationship to the study drug(s) (suspected/not suspected) 
 its duration (start and end dates or if continuing at final exam) 
 action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
 whether it constitutes a serious adverse event (SAE) 
 
All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure or will be communicated between Investigator Brochure 
updates in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
9.1.1  Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 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. 
 
9.2  
Adverse Events of Special Interest (AESI) 


36 
 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events (regardless of seriousness) will be reported to Pharmacyclics 
Drug Safety per the SAE reporting timelines.  
9.2.1  Major Hemorrhage  
Major hemorrhage is defined as any of the following: 
 Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. Any 
treatment-emergent serious adverse events of bleeding of any grade 
 Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or 
higher AE per CTCAE vX.X. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.6 above. 
 
9.3 
Serious adverse events 
All serious adverse events and AESIs (initial and follow-up information) will be reported on 
FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB 
Reporting Form and sent via email (drugsafety@pcyc.com) or fax  (408-215-3500) to 
Pharmacyclics Drug Safety, or designee, within 24 hours of the event. Pharmacyclics may 
request follow-up and other additional information from the Sponsor Investigator. 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
 The event resolves; 
 The event stabilizes; 
 The event returns to baseline, if a baseline value/status is available; 
 The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct; 
 It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts). 
 
9.3.1 SAE Definition 
An SAE is any adverse event, without regard to causality, that is life-threatening or that 
results in any of the following outcomes: death; in-patient hospitalization or prolongation 
of existing hospitalization; persistent or significant disability or incapacity; or a 
congenital anomaly or birth defect. Any other medical event that, in the medical 
judgment of the principal investigator, may jeopardize the subject or may require medical 
or surgical intervention to prevent one of the outcomes listed above is also considered an 
SAE. A planned medical or surgical procedure is not, in itself, an SAE. Also specifically 
excluded from this definition of SAE is any event judged by the principal investigator to 


37 
 
represent progression of the malignancy under study, unless it results in death within the 
SAE Reporting Period. 
 
9.3.2 SAE Reporting Period 
The SAEs that are subject to this reporting provision are those that occur from after the 
first dose of the Study Drug through 30 days after discontinuation of the Study Drug.   
 
9.4 
Pregnancy 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Pharmacyclics within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities or maternal and newborn complications. 
 
9.5 
Data safety monitoring plan 
Data including adverse events will be entered into Oncore. The participating investigator will 
report all adverse events to the protocol chair and to the IRB according to the local IRB’s 
policies and procedures in reporting adverse events. The protocol chair has the obligation to 
report all SAE to the FDA and IRB. SAE and AESI will be also reported to Pharmacyclics Drug 
Safety per the SAE reporting timelines. 
10. 
Data collection 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a protocol case number. This number is unique to the participant on this trial and must 
be used for case report form (CRF) completion in Oncore. 
Investigators must enter the information required by the protocol onto CRFs. 
11. 
Quality of Life Assessment 
Patient quality of life will be measured using the EORTC QLQ-C30 (version 3) and the EORTC 
QLQ GI.NET21 questionnaires (appendices B and C).  The EORTC QLQ-C30 questionnaire is 
designed to assess the health-related quality of life of cancer patients participating in clinical 
trials.  It is composed of 5 functional scales, three symptom scales, a global health status scale, 
and six single items.  The EORTC QLQ GI.NET21 questionnaire is designed to assess physical 
and psychological symptoms related to neuroendocrine tumors of the gastrointestinal tract. 
Both questionnaires will be scored and handled as recommended in the user manual.  Missing 
items will be imputed with the mean of the non-missing items scored at that assessment time 
point.  Ambiguous items will be considered as missing items.  At each assessment time point, 
summary statistics of the raw score and linear transformation score (on a 0-100 scale) will be 
provided. 


38 
 
12. 
Publication of trial results 
Publications resulting from this trial may be developed by the investigator who will provide 
Pharmacyclics an opportunity (within 30 days before submission or other public disclosure) to 
prospectively review any proposed publication, abstract or other type of disclosure that reports 
the results of the study. 
13. 
Regulatory considerations 
13.1 Protocol review and amendments 
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed and approved by a properly constituted IRB governing the study 
location. 
Any change or addition (excluding administrative) to the study protocol or informed consent 
form protocol must be submitted as amendments and must be reviewed and approved by 
Pharmacyclics prior to submission to the IRB and the investigator before implementation.  
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB. Any changes in study 
conduct must be reported to the IRB. The Principal Investigator will disseminate protocol 
amendment information to all participating investigators. 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
13.2 Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB approval. The original signed copy of the consent document must be 
retained in the medical record or research file. 


39 
 
13.3 Committees 
13.3.1 
Scientific Review Committee (SRC) 
Each SRC conducts a formal internal peer review of all clinical protocols and general scientific 
oversight of interventional clinical research. Protocols are reviewed for scientific merit, adequate 
study design, safety, availability of targeted study population, and feasibility of timely 
completion of all proposed research projects to be conducted by its assigned programs at the 
Cancer Center. Each SRC is responsible for evaluation the risk/benefit assessment and 
corresponding data and safety monitoring plan as part of the scientific review and approval 
process. 
13.3.2 
Data Safety Monitoring Committee (DSMC) 
The DSMC will meet on a monthly basis and will continually assess for subject safety and 
recommend changes to protocol and study as required to preserve subject safety and prevent any 
untoward toxicity. 
13.3.3 
Protocol monitoring Committee (PMC) 
This study will be reviewed by the PMC for data and safety monitoring. The PMC monitors its 
assigned ongoing research protocol for: adverse event reporting, data and safety monitoring, and 
internal audit findings. The PMC, upon review of any agenda item, may approve the study for 
continuation, require revisions, suspend or close a protocol. 
13.4 Internal monitoring 
The trial will be monitored per Moffitt Cancer Center policy MRI-P.PSO.03, Monitoring of 
Investigator Initiated Clinical Research. Data will be captured in Oncore, Moffitt’s Clinical 
Trials Database, Regulatory documents and case report forms will be monitored internally 
according to Moffitt Cancer Center Monitoring Policies. Monitoring will be performed regularly 
to verify data is accurate, complete and verifiable from source documents; and the conduct of the 
trial is in compliance with the currently approved protocol/amendments, Good Clinical Practice, 
and applicable regulatory requirements. 
13.5 Ethics and Good Clinical Practice (GCP) 
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, informed consent forms, and other relevant documents, e.g., 
advertisements, if applicable, from the IRB/IEC.  The trial will be performed in accordance with 
the protocol, International Conference on Harmonization Good Clinical Practice guidelines, and 
applicable local regulatory requirements and laws. 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy. 
13.6 Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 


40 
 
or 
can 
be 
accessed 
via 
the 
website 
of 
the 
World 
Medical 
Association 
at 
http://www.wma.net/e/policy/17-c_e.html. 
13.7 Study documentation 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays. 
13.8 Retention of records 
Retained records will include all documentation of adverse events, records of study drug receipt 
and dispensation, and all IRB correspondence for at least 5 years after the investigation is 
completed. 
 
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Vauthey JN, Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and 
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44 
 
APPENDIX A: 
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general categorization into 
strong, moderate, and weak inhibitors according to the website is displayed below. Refer to Section 5.2 on 
instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib. 
 
 
 


45 
 
Appendix B: EORTC QLQ-C30 (version 3)  
 


46 
 
 
 
 
 


47 
 
Appendix C EORTC QLQ-GLNET21  
 
 


48 
 
Appendix D 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:  
1. 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, Pietroni MC, Williams R . “Transection of te 
oesophagus for bleeding oesophageal varices”.  The British journal of surgery, 1973;60: 646-9.