Conditions: Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
This randomized pilot clinical trial studies the side effects and best dose of naloxegol and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer. Naloxegol may relieve some of the side effects of opioid pain medication and fight off future growth in the cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine feasibility and safety of long-term administration of two doses of a peripheral opioid receptor antagonist in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line systemic therapy.

SECONDARY OBJECTIVES:

I. To explore whether patients randomized to one or both of the two study drug arms have less decline in health-related quality of life (HRQoL) than patients randomized to placebo.

II. To estimate the difference in the pain levels and opioid/non-opioid analgesic requirements between patients receiving naloxegol or placebo.

III. To estimate the difference in the adverse peripheral effects of opioids (e.g. constipation, nausea/emesis, dry mouth and urinary retention) between patients receiving naloxegol or placebo.

IV. To explore whether there is a signal that naloxegol may be associated with longer progression-free survival (PFS) and overall survival (OS).

V. To evaluate the difference in discontinuation rate of systemic therapy due to adverse events (AEs) and deaths attributable to systemic therapy.

After completion of study treatment, patients are followed up every 3 months.

Arms:
arm 1: Patients receive lower dose naloxegol PO QD and placebo PO QD. Courses repeat every 3 weeks in year 1 and then every 3 months in year 2 in the absence of unacceptable toxicity. arm 2: Patients receive placebo PO QD and higher dose naloxegol PO QD. Courses repeat every 3 weeks in year 1 and then every 3 months in year 2 in the absence of unacceptable toxicity. arm 3: Patients receive placebo PO QD. Courses repeat every 3 weeks in year 1 and then every 3 months in year 2 in the absence of unacceptable toxicity.

Interventions: intervention 1: Naloxegol intervention 2: Placebo intervention 3: Laboratory Biomarker Analysis intervention 4: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 






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A Randomized, Double-Blind, Placebo-Controlled Pilot Study of an Oral, Selective Peripheral 
Opioid Receptor Antagonist in Advanced Non-Small Cell Lung Cancer  
Eligibility Criteria (see Section 3.2) 
Required Initial Laboratory Values 
Advanced (stage IIIB or IV) non-small cell lung cancer. See 3.2.1  
No known presence of known EGFR or EML4-ALK driver mutations in the tumor 
Absolute neutrophil 
count (ANC) 
≥ 1500/mm3 
Started first-line systemic therapy of the investigator’s choice within 12 weeks prior  
Platelet Count 
≥ 100,000/mm3 
to registration, or planning to initiate first-line systemic therapy of the 
investigator’s choice within 4 weeks after registration. . See 3.2.3. 
Calc. Creatinine 
≥ 60 mL/min* 
No prior systemic therapy for advanced NSCLC (other than current treatment). See 
3.2.4.  
Clearance (see 
Alliance website)     
 
No current or prolonged recent use of mixed opioid agonists/antagonists or other 
opioid antagonists. See 3.2.5 
Total Bilirubin 
≤ 1.2 x ULN** 
No methadone within 4 weeks prior to registration. 
Patients must have used opioid medication(s) for pain at some time in the 4 weeks 
prior to registration.  See 3.2.7. 
AST and ALT 
≤ 2.5 x ULN 
Expected survival > 3 months. 
* Calculated using the Cockcroft-Gault 
No concurrently active second invasive malignancies except non-melanoma skin 
formula 
cancer. See 3.2.9. 
   **Unless due to Gilbert’s disease 
No history of gastrointestinal obstruction or conditions that increase the risk of  
   
gastrointestinal obstruction, perforation, bleeding or impairment of the 
 
gastrointestinal wall. No abdominal surgery within 60 days of registration. 
 
No acute gastrointestinal conditions. See 3.2.11 
 
No conditions that may compromise blood-brain barrier permeability. See 3.2.12 
 
 
No history of myocardial infarction ≤ 6 months prior to registration. See 3.2.13. 
 
 
No severe hepatic impairment (Child-Pugh class C), or acute liver disease. 
 
 
No known serious or severe hypersensitivity reaction to naloxegol or any of its 
 
 
excipients 
 
 
No concurrent use of moderate/strong CYP3A4 inhibitors, strong CYP3A4 
inducers, or other opioid antagonists or mixed agonists/antagonists. See 3.2.16. 
 
 
Not pregnant and not nursing. See 3.2.17. 
 
 
Age ≥ 18 years 
 
 
ECOG Performance Status 0-2 
 
 
 
Schema 
1 Cycle = 3 weeks during the first year of treatment 
1 Cycle = 3 months during the second year of treatment 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
Naloxegol 12.5 mg 
orally once daily 
 
 
 
 
Naloxegol 25 mg 
orally once daily 
 
 
 
 
Placebo 
orally once daily 
 
 
 
Treatment is to continue for up to 2 years, but it can be discontinued for unacceptable adverse events. 
Clinic visits will take place at 3 and 6 weeks and then every 6 weeks for 1 year following the start of 
treatment. Patients will then be followed every 3 months until 2 years after the start of treatment.  
Administration of standard opioids and other analgesics to control pain adequately will be permitted in all 
patients at the discretion of the treating physician. 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 


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TABLE OF CONTENTS 
 
Section 
Page 
1.0 
BACKGROUND .............................................................................................................................. 7 
1.1 
Rationale for Proposed Study ......................................................................................................... 7 
1.2 
Rationale for selecting lung cancer ................................................................................................ 7 
1.3 
Rationale for selecting feasibility and safety as the primary endpoint: .......................................... 8 
1.4 
Rationale for estimating change in HRQoL in the current study ................................................... 8 
1.5 
Rationale for selecting baseline levels/presence/absence of pain, opioid use and peripheral 
adverse effects of opioids: ........................................................................................................................ 9 
1.6 
Rationale for a 3-arm study design including placebo and 2 dose arms of study drug: ............... 11 
1.7 
Basic and pre-clinical studies ....................................................................................................... 12 
1.8 
Naloxegol and other PAMORAs .................................................................................................. 14 
1.9 
 Study Hypotheses ........................................................................................................................ 15 
1.10 How this pilot study will provide essential data for a future, more definitive study, and its 
possible design:....................................................................................................................................... 15 
2.0 
OBJECTIVES ................................................................................................................................ 16 
2.1 
Primary objective ......................................................................................................................... 16 
2.2 
Secondary objective(s) ................................................................................................................. 16 
2.3 
Correlative science objective ........................................................................................................ 16 
3.0 
PATIENT SELECTION ............................................................................................................... 16 
3.1 
On-Study Guidelines .................................................................................................................... 16 
3.2 
Eligibility Criteria......................................................................................................................... 17 
4.0 
PATIENT REGISTRATION ....................................................................................................... 20 
4.1 
CTEP / DCP Investigator Registration Procedures ...................................................................... 20 
4.2 
CTSU Site Registration Procedures ............................................................................................. 21 
4.3 
Patient Registration Requirements ............................................................................................... 23 
4.4 
Patient Registration/Randomization Procedures .......................................................................... 23 
4.5 
Registration to Correlative and Companion Studies .................................................................... 24 
4.6 
Stratification Factors .................................................................................................................... 24 
4.7 
Procedures for Double-Blinding the Treatment Assignment ....................................................... 24 
5.0 
STUDY CALENDAR .................................................................................................................... 25 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 26 
6.1 
Data Collection and Submission .................................................................................................. 26 
6.2 
Specimen collection and submission ............................................................................................ 28 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 31 
7.1 
Naloxegol/ Placebo ....................................................................................................................... 31 
7.2 
First-line systemic therapy. .......................................................................................................... 32 
7.3 
Opioids ......................................................................................................................................... 32 
8.0 
DOSE AND TREATMENT MODIFICATIONS & UNBLINDING ........................................ 32 
8.1 
Ancillary therapy, concomitant medications, and supportive care ............................................... 32 
8.2 
Dose Modifications ...................................................................................................................... 34 
8.3 
Unblinding Procedures ................................................................................................................. 35 
9.0 
ADVERSE EVENTS ..................................................................................................................... 36 
9.1 
Routine adverse event reporting ................................................................................................... 36 
9.2 
CTCAE Routine Reporting Requirements ................................................................................... 37 


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9.3 
Expedited Adverse Event Reporting (CTEP-AERS) ................................................................... 37 
10.0 
DRUG INFORMATION ............................................................................................................... 40 
10.1 Naloxegol (IND Exempt) ............................................................................................................. 40 
10.2 Placebo ......................................................................................................................................... 43 
11.0 
HEALTH OUTCOMES MEASURES ......................................................................................... 43 
11.1 FACT-L ........................................................................................................................................ 43 
11.2 PRO-CTCAEs and urinary hesitancy question ............................................................................ 44 
11.3 Bowel function-diary (BF-Diary) ................................................................................................. 44 
11.4 Pain and analgesic use .................................................................................................................. 44 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................... 45 
12.1 Duration of Treatment .................................................................................................................. 45 
12.2 Managing ineligible patients and registered patients who never receive protocol intervention ... 45 
12.3 Extraordinary Medical Circumstances ......................................................................................... 45 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 45 
13.1 Study Overview ............................................................................................................................ 45 
13.2 Sample Size, Accrual Time and Study Duration .......................................................................... 46 
13.3 Statistical Design and Analysis for the Primary Endpoint ........................................................... 47 
13.4  Supplementary Analysis Plans ..................................................................................................... 47 
13.5  Study Monitoring ......................................................................................................................... 48 
13.6  Study Reporting ............................................................................................................................ 49 
13.7 Inclusion of Women and Minorities ............................................................................................. 50 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 51 
14.1 Biological mechanism of action, and biomarkers that would predict response/risk to the study 
drug  ...................................................................................................................................................... 51 
15.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ...................... 56 
16.0 
REFERENCES .............................................................................................................................. 57 
17.0 MODEL CONSENT FORM ............................................................................................................ 63 
APPENDIX I: PAIN AND PAIN MEDICATION DIARY ................................................................... 75 
APPENDIX II: PATIENT MEDICATION DIARY – NALOXEGOL/PLACEBO............................ 79 
APPENDIX III: CALCULATION OF EQUI-ANALGESIC DOSES OF OPIOID MEDICATIONS .  
 
 ......................................................................................................................................................... 81 
APPENDIX IV: BOWEL FUNCTION-DIARY (BF-DIARY) ............................................................. 83 
APPENDIX V: PRO-CTCAE* AND URINARY HESITANCY QUESTION .................................... 85 
APPENDIX VI: FACT-L (VERSION 4) ................................................................................................ 88 
APPENDIX VII: PATIENT INFORMATION SHEETS ...................................................................... 91 
APPENDIX VIII: HEMOLYZED PLASMA SAMPLES ..................................................................... 97 
APPENDIX IX: NALOXEGOL WALLET CARD ............................................................................... 98 
 


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1.0 
BACKGROUND 
1.1 
Rationale for Proposed Study 
Opioid medications are the mainstay of treatment for severe, chronic cancer pain. The analgesic 
activity of opioids is mediated via central mu opioid receptors (MORs) in the central nervous 
system (CNS). However, MORs are also present on endothelial cells1 and in human tumors 
(peripheral MORs), including lung2-4 and prostate5 cancer. Compelling pre-clinical studies 
indicate that expression and activation of peripheral MORs are associated with tumor 
progression in animal models. Recent clinical studies raise the possibility that opioid exposure 
is also associated with tumor progression in patients with various malignancies including lung 
cancer. See section 1.7. In patients with advanced malignancies, symptoms related to 
progression of cancer and its treatments, as well the adverse effects of commonly used opioids, 
all contribute to impair the health-related quality of life (HRQoL). 
In view of the above, our long-term goal is to develop a novel, non-chemotherapeutic 
intervention blocking the activation of peripheral opioid receptors that contributes to tumor 
progression and adverse effects of opioids may improve the HRQoL of patients with advanced 
malignancies, and may also improve disease outcomes. Towards this eventual goal, we will 
perform this pilot study to first determine the feasibility and safety of long-term administration 
of an orally available, FDA-approved, peripherally acting mu opioid receptor antagonist 
(PAMORA) in a patient population receiving standard systemic therapy for advanced, incurable 
lung cancer. We hope to eventually study this agent in a more advanced phase clinical trial. 
1.2 
Rationale for selecting lung cancer  
Worldwide, lung carcinoma is the most common malignancy and the leading cause of cancer 
deaths. The global incidence of lung cancer was estimated to be 1.8 million cases/year in 2012, 
resulting in nearly 1.6 million deaths/year (nearly 20% of all cancer deaths).6 In the United 
States, the incidence of lung cancer is projected to be 224,390 new cases in 2016, which will 
lead to approximately 158,000 deaths (26.5% of all cancer deaths).7 The majority (≥ 80%) of 
lung cancers are non-small cell lung cancer (NSCLC), of which adenocarcinoma is the most 
common subtype.  
Advanced malignancies, including NSCLC, are often accompanied by pain. Approximately 2/3 
of patients with advanced malignancies experience pain, with 50% experiencing at least 
moderate pain; lung cancer ranks third highest for pain prevalence among all malignancies.8  
Malignancy options that were considered for the current study included (a) patients with various 
advanced malignancies, or (b) patients with a single tumor type (non-small cell lung cancer, 
pancreatic, breast or prostate cancer). Including patients with diverse malignancies would 
accelerate accrual and generalization of the results, but we were concerned that heterogeneity in 
this patient population and their cancer treatments would have an insurmountable impact on 
statistical analysis of adverse effects and activity. Advanced pancreatic cancer is common, often 
presents with inoperable/incurable disease in which survival is relatively short, and is associated 
with severe, refractory pain. However, there is a lack of basic, pre-clinical or clinical data 
relevant to the current concept. Breast and prostate cancer were not considered as the optimal 
malignancies to study because long survival of patients with both of those malignancies will 
require very prolonged follow-up to detect possible benefit.  
The clinical course and prognosis of the various subtypes of NSCLC including adenocarcinoma, 
large cell carcinoma and squamous cell carcinoma are similar (overall response rate of ~30%, 
time to progression of 4-6 months, 1-year survival of 30-40% and 2 year survival of 10-15%). 
Impairment of HRQoL (the primary endpoint of this study) is therefore likely to occur at similar 
time points in patients with adenocarcinoma as in patients with other subtypes of NSCLC. 


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Several groups (including ours) have reported that pain/opioids/peripheral opioid receptor 
activation is associated with poorer outcomes (including shorter survival) in cohorts of NSCLC 
patients including both adenocarcinoma and other subtypes.24, 47, 48, 49, 58, 59, 93  We and others have 
also reported that similar effects occur in diverse malignancies, including those of the prostate, 
breast, pancreas, esophagus, stomach, colon.5, 48, 53-59, 94, 95 Therefore, the evidence indicates that 
the association of peripheral opioid receptor activation with poorer clinical outcomes is likely 
to be a phenomenon that occurs in many common malignancies, and is not restricted to 
adenocarcinoma of the lung. 
When this study was initially designed, the standard systemic therapy for adenocarcinoma of 
the lung was a combination of a platinum (cisplatin or carboplatin) and pemetrexed, so we 
accordingly restricted eligibility to adenocarcinoma alone. However, the field has advanced 
rapidly, and current standard therapy for adenocarcinoma as well as other subtypes of NSCLC 
includes immune checkpoint inhibitor alone (e.g. pembrolizumab) for all subtypes of NSCLC 
where tumor PD-L1 expression is ≥50%, and a combination of immune checkpoint inhibitor 
therapy with platinum-based chemotherapy in all subtypes of NSCLC where tumor PD-L1 
expression is ≥1%. While pemetrexed itself is not recommended for patients with squamous cell 
carcinoma, the other commonly used standard platinum-based regimens are all Category 1 
options common to adenocarcinoma and squamous cell carcinoma (e.g. those including 
paclitaxel, docetaxel, etoposide or gemcitabine: NCCN Guidelines version 6.2018 for Non-
Small Cell Lung Cancer). For the above reasons, we believe that it is no longer necessary to 
restrict eligibility to adenocarcinoma of the lung, and that patients with other subtypes of 
NSCLC receiving standard first-line systemic therapy should also be eligible. 
We therefore elected to limit this study to patients with advanced NSCLC, because (a) it is a 
very common tumor type, (b) patients often present with advanced (incurable) disease associated 
with relatively short survival, (c) there is extensive basic and pre-clinical data available 
regarding opioid receptor expression and activity that provides a solid scientific basis for this 
study, as well as retrospective clinical data showing association of opioid exposure with poorer 
clinical outcomes, and (d) tumor progression (that usually occurs within 5-8 months of starting 
first-line chemotherapy9) impairs HRQoL.10-12 For the above reasons, we expect to reach the 
primary endpoints relatively quickly in this pilot study. See section 1.7. 
1.3 
Rationale for selecting feasibility and safety as the primary endpoint: 
In an initial pilot study, it is most important to determine if (a) a sufficiently high accrual rate 
will be achieved in a diverse multi-center setting to make it possible to successfully undertake a 
larger, more definitive study, (b) the majority of patients will be able to continue taking the study 
drug together with systemic therapy for an extended period, (c) the study drug is associated with 
an acceptably low rate of severe (grade III or higher) side effects in this setting, and (d) there is 
any signal that administration of the study drug may be associated with unexpected adverse 
clinical outcomes when given together with systemic therapy. 
Of note, several pre-clinical studies from study team and others demonstrating that PAMORAs 
inhibit morphine-induced upregulation of angiogenesis and multi-drug resistance to 
chemotherapy13-14 provide reassurance that the study drug is not likely to adversely affect the 
efficacy of systemic therapy. 
1.4 
Rationale for estimating change in HRQoL in the current study 
Tumor progression is known to impair, and effective chemotherapy is known to improve, 
HRQoL in advanced NSCLC.11-12 Early initiation of non-chemotherapeutic interventions (e.g., 
palliative care) in patients with advanced NSCLC further improves HRQoL, irrespective of anti-
cancer therapies.15  


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The HRQoL of patients with advanced malignancies is adversely affected by pain and other 
symptoms due to tumor progression as well as by the adverse peripheral effects of opioid 
analgesics, including constipation, nausea, vomiting, xerostomia and drowsiness.16 Recent 
studies further suggest that opioid-associated tumor progression may be an additional factor that 
impairs HRQoL. 
In patients with advanced non-squamous NSCLC (adenocarcinoma), pemetrexed-based 
chemotherapy achieves a median progression-free survival (PFS) of 5.3 (95% CI: 4.8-5.7) 
months, with a median overall survival (OS) of 12.6 months; approximately 75% patients remain 
alive at 6 months.17 Pemetrexed-based induction chemotherapy followed by maintenance 
pemetrexed achieves a median PFS of 4.4 (95% CI: 4.1-5.7) months from randomization to 
maintenance pemetrexed,18 or 7.5 (95% CI: 6.9-8.6) months from the start of initial induction 
chemotherapy.9  
Overall HRQoL (total FACT-L score) and the trial outcome index (TOI) of patients with 
advanced NSCLC treated with standard induction chemotherapy declines significantly by 6 
months.19 A more recent HRQoL analysis of patients receiving pemetrexed maintenance 
chemotherapy for NSCLC found that the time to worsening of symptoms (TWS) for pain 
occurred at a median of 6.1 (95% CI: 4.6 – 9.6) months and TWS for overall HRQoL occurred 
at a median of 5.8 (95% CI: 4.4 – 8.4) months from randomization to maintenance pemetrexed 
(please see figure 1).10 Of note, there was a rapid decline in HRQoL within the first few months 
of starting maintenance pemetrexed (i.e., after 3 months of prior induction chemotherapy). 
In the above study, there was a highly significant correlation between TWS of pain or HRQoL 
and progression-free survival and overall survival (P < 0.0001) for all comparisons, indicating 
that worsening of pain and HRQoL coincide with disease progression and death.10 The Food and 
Drug Administration (FDA) and the American Society of Clinical Oncology (ASCO) have 
opined that determining the effect of treatment on symptoms and HRQoL is of major importance 
in advanced NSCLC.20,21 Accordingly, HRQoL has been used as a primary endpoint in recent 
phase III trials comparing pemetrexed based chemotherapy with other regimens in NSCLC.22,23  
For the above reasons, HRQoL may therefore serve as the “best” overall measure of potential 
benefit of the study drug with respect to mitigation of opioid-induced tumor progression as well 
as mitigation of the peripheral adverse effect of opioids. In view of the expected PFS, OS and 
time to decline in HRQoL in advanced NSCLC (detailed above), we propose to estimate the 
difference in HRQoL at 6 months in this pilot study, to inform the design of the subsequent 
phase II or III studies. Patients may experience objective progression of disease by this time,9,18 
but naloxegol/placebo will be continued for up to 2 years, and data will continue to be collected 
regarding the safety and potential efficacy of the study drug during this time, even in patients 
who progress on first line therapy. See Section 1.7. The Alliance has considerable experience in 
ensuring continued data collection by mail or phone in patients who become unable to come to 
clinic visits because of clinical deterioration, so we expect the drop-out rates for HRQoL data 
collection to be relatively low for the proposed duration. 
1.5 
Rationale for selecting baseline levels/presence/absence of pain, opioid use and peripheral 
adverse effects of opioids: 
Inclusion/exclusion criteria regarding pain and opioid use prior to registration/initiation of 
study:  
We considered various options, including (a) limiting the study to patients with minimal pre-
study pain and little/no opioid use, (b) limiting the study to patients with high levels of pain and 
extensive opioid use, or (c) not requiring patients to be experiencing a specific level of pain, but 
only requiring patients to have needed opioid medication(s) for pain within 4 weeks of 
registration.  


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Option (a) would minimize the theoretical likelihood that pain/opioids would have impacted on 
tumor biology prior to initiation of study drug, but might delay detection of improvement in 
HRQoL endpoints.  
Option (b) would increase likelihood of early detection of improvement in HRQoL, but would 
also increase likelihood of GI side effects of the study drug (due to a rapid reversal of 
constipation). Such patients may also be too ill to stay on the study for sufficient length of time 
and experience short survival, compromising their contribution to provide adequate longer-term 
data on the endpoints being studied. Furthermore, potential benefit of study drug may not be 
seen because pain/opioids may already have induced tumor angiogenesis/signaling pathways 
causing tumor progression.  
Considering all these aspects, we initially selected option (c) because it was suggested by 
reviewers, that we do this when an early version of this protocol concept was reviewed, it might 
achieve the best possible balance between testing the underlying pathophysiological 
phenomena, facilitate rapid enrollment, allow for widest possible applicability of the results, and 
allow detection of improvement in HRQoL during the planned duration of the study (please see 
section on HRQoL above, and Figure 1 for the basis for this expectation), since patients would 
have started requiring opioid medications for pain control already. We did not expect this 
criterion to create a significant barrier to enrollment, since, in our recent study24 the majority of 
patients with advanced NSCLC had required opioids prior to initiation of chemotherapy. 
Inclusion/exclusion 
criteria 
regarding 
opioid-induced 
adverse 
effects 
prior 
to 
registration/initiation of study:  
The study design includes specifically and prospectively assessing the separate impact of 
naloxegol on constipation (using a validated opioid-induced constipation [OIC] instrument) and 
other side effects of opioids (using Linear Analogue Self-Assessment [LASA] and Patient-
Reported Outcome - Common Terminology Criteria for Adverse Events [PRO-CTCAE] items) 
as they may arise over time, so that the results of this pilot study will provide an exploratory 
assessment of the effect of naloxegol on diverse side effects of opioids in cancer patients, and 
directly inform the design of a future definitive study. While the patients who we enter on this 
trial may not have a large number of symptoms or a poor HRQoL at baseline, we fully expect 
that HRQoL will decrease over time as the lung cancer disease becomes more prominent. Thus, 
we will have patients who could give a positive HRQoL signal due to beneficial effects on 
cancer-related symptoms, and perhaps also on peripheral adverse effects of opioids as they arise 
in patients who require escalating opioid doses with cancer progression (see section on HRQoL 
above, and Figure 1). 
 


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1.6 
Rationale for a 3-arm study design including placebo and 2 dose arms of study drug: 
Why a pilot study is needed: 
Data are not available on long-term administration of naloxegol in patients with advanced 
malignancies receiving chemotherapy.  
Specifically, what is not known is: (a) if a sufficiently high accrual rate will be achieved to a 
study of a PAMORA in patients with advanced malignancy, (b) what proportion of patients can 
take the study drug together with chemotherapy or other first-line systemic therapy, (c) the 
length of time patients can stay on the study drug together with systemic therapy, (d) the 
frequency of severe adverse effects of the study drug, and rate of discontinuation, when given 
with systemic therapy (d) if there is any signal that the study drug may be associated with 
unexpected clinical outcomes when given together with systemic therapy, (e) the length of time 
patients will be compliant with completing HRQoL and other questionnaires in this setting, and 
(f) if PAMORAs will improve HRQoL, as HRQoL has not been directly assessed in the 
retrospective clinical studies of PAMORAs thus far. 
It will be advisable to ascertain the feasibility and safety of administering naloxegol at selected 
doses in patients receiving systemic therapy for advanced NSCLC, before committing greater 
resources and a larger number of patients to a phase II or III study. We propose to conduct a 
pilot, placebo-controlled trial of two FDA-approved doses of naloxegol. This pilot trial will test 
the feasibility of the study design, provide reassurance regarding the tolerability and safety with 
systemic therapy of at least one of the two doses of naloxegol in this patient population, and 
perhaps provide a signal regarding efficacy, to inform the design of a subsequent definitive 
study. Further, the effect of PAMORA medications (e.g. naloxegol) on HRQoL in cancer 
patients needs to be evaluated prospectively, which we propose to initiate in this pilot study. 
Use of placebo: A placebo design is essential to provide a control arm for comparison of 
potential adverse effects and possible activity (difference in HRQoL between the study drug 
arms and placebo) of the study drug, although it will increase the sample size. 
Use of a 3-arm design: The commonly used phase I type study design (sequential testing of 
escalating doses of study drug) will not be optimal for the current study because (a) it will not 
permit inclusion of a placebo arm, and (b) it will not lend itself well to assessment of [i] relative 
safety in patients receiving systemic therapy, i.e., relative frequency of systemic therapy side 
effects and discontinuation in patients receiving systemic therapy without vs with naloxegol, or 
[ii] efficacy of the study drug with respect to improvement in HRQoL. We therefore elected to 
use a study design that allows randomization to placebo or one of two doses of the study drug. 
We have used this design previously.29,30  
We propose to test two doses of the study drug to increase the likelihood of identifying an 
“optimal” dose, and reduce the likelihood of missing an activity signal because of insufficient 
dosing (if dosing is based on prior studies where amelioration of opioid-induced constipation 
was the primary endpoint). We recognize that testing two doses will increase the sample size, 
and the higher dose may be associated with more adverse effects. Using a placebo and 2 doses 
of the study drug will still be possible with a sample size of ~200 patients, which is feasible in 
this setting. 
We considered several approaches regarding the number of doses (1, 2 or 3) of the study drug 
to test, before selecting the current 2-dose design: 
Testing one dose will require the smallest sample size. However, it may miss potential activity 
of naloxegol on inhibiting morphine-induced tumor progression, since the currently approved 
lower dose (12.5 mg/day) is based on activity in ameliorating opioid-induced constipation. 
Mechanisms such as higher levels of drug efflux from malignant cells may require a higher dose 
for optimal activity against tumor progression. 


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Testing three doses will increase the likelihood of identifying an “optimal” dose, and reduce the 
likelihood of missing an activity signal because of insufficient dosing (if dosing is based on prior 
studies where amelioration of opioid-induced constipation was the primary endpoint). However, 
this will considerably increase sample size, and a dose higher than the FDA-approved doses may 
be associated with more adverse effects. 
We therefore elected to test two FDA-approved doses of naloxegol, to achieve the best possible 
balance between improving the chances of identifying possible activity against tumor 
progression, while maintaining tolerability/safety and limiting the total sample size. 
1.7 
Basic and pre-clinical studies  
Studies in animal models 
Pre-clinical studies from our group and others have shown that morphine and other opioids, in 
clinically relevant doses, promote cancer growth and metastasis by stimulating pro-angiogenic, 
survival- and growth- promoting signaling in endothelium.1,31,32 We also showed that chronic 
morphine treatment stimulates angiogenesis, tumor growth and metastasis, and impairs survival, 
in mouse models of breast cancer.1,31 In a mouse model that spontaneously develops breast 
cancer and mimics the evolutionary spectrum of human breast cancer, we found that morphine 
activates mast cells and lymphangiogenesis in the tumors, while promoting tumor progression 
and shortening survival.33 The relevance of this finding is further supported by observations 
from our laboratory and others that the opioid receptor antagonists, including naloxone, inhibit 
breast cancer growth in rodents.1,34-37 However, naloxone cannot be used clinically in this 
context because it antagonizes the analgesic effect of opioids. 
Studies in lung cancer 
Our group has shown that MORs and receptor tyrosine kinases (RTKs) are expressed and co-
localized in advanced lung cancer, and that morphine induces RTK activation and signaling, 
leading to growth and spread of lung cancer cells.2 These human lung cancer cells, as well as 
primary lung adenocarcinomas showed significantly increased expression of MOR (mu opioid 
receptors) as compared to control Beas-2B cells and normal lung tissue. Concurrently, 
complementary studies by members of our study team demonstrated that MOR silencing of 
Lewis lung carcinoma cells (LLC) led to decreased metastasis in mice, and that MOR knockout 
mice did not develop significant LLC tumor growth as compared to wild type 
mice.4 Importantly, pharmacological treatment with methylnaltrexone (a PAMORA) inhibited 
LLC invasion in soft agar and LLC tumor volume and metastasis in mice.4 Subsequent studies 
by our study team showed that overexpression of MOR in human lung cancers promotes tumor 
growth and metastases in xenografts in mice.38 More recently we showed that morphine, acting 
via MOR, upregulates multi-drug resistance to chemotherapeutic agents in human NSCLC cells; 
this effect is blocked by the PAMORA methylnaltrexone.13 Together, these preclinical data 
provide compelling evidence for the role of MOR in lung cancer progression and metastasis; 
and amelioration of lung cancer progression and metastasis with strategies utilizing inhibition 
of MOR including antagonism with a PAMORA.  
Taken together, these pre-clinical studies provide strong evidence that in animal models of 
several malignancies, activation of peripheral MORs (on endothelial cells and tumors, not in the 
CNS), by clinically used opioid medications, promotes tumor progression via several different 
mechanisms including Stat3, MAPK/ERK and Akt phosphorylation, nitric oxide synthesis, 
COX-2 activation, PGE2 production, cross-activation of EGFR and VEGF-R2, substance P (SP) 
and mast cell activation.14,31-33,38-42 Notably, these mechanisms play a central role in cancer 
progression as well as nociception. More recently, Suzuki et al. have shown that the peripheral 
opioid receptor antagonist methylnaltrexone augments the antineoplastic activity of the 


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chemotherapeutic agent docetaxel and improves survival in a mouse xenograft model of human 
gastric cancer.43  
Human studies 
In a retrospective study involving patients with advanced prostate cancer receiving androgen 
deprivation therapy, we found that greater opioid requirement and higher levels of MOR 
expression in the tumor specimen are independently associated with shorter progression-free 
survival and overall survival.5 More recently, Halabi et al. confirmed and extended our findings 
to patients with advanced prostate cancer receiving first-line docetaxel-based chemotherapy on 
CALGB study 90401 and the ENTHUSE-33 trial, reporting that opioid use is an independent 
prognostic factor for survival.44  
In a retrospective NSCLC study, we examined if long-term opioid requirement, independently 
of chronic pain, is associated with survival.24 We analyzed 209 patients diagnosed with stage 
IIIB/IV NSCLC and treated with standard chemotherapy. The effects of pain, opioid 
requirement, and known prognostic variables on outcomes were analyzed in univariable and 
multivariable models. Both the severity of chronic pain and greater opioid requirement after 
starting chemotherapy were strongly associated with shorter OS by univariate analysis. The 
survival of patients experiencing lower levels of chronic pain and requiring lower doses of 
opioids (LPLO group) was markedly longer than the survival of patients experiencing higher 
levels of chronic pain and/or requiring higher doses of opioids in the period from starting 
chemotherapy until death/last follow up (median overall survival, 16.4 vs ~7 months, p ≤ 0.001). 
Remarkably, the level of pain experienced and opioid analgesics required during the first 3 
months after diagnosis were strongly predictive of survival. Patients in the LPLO group during 
the first 3 months after starting chemotherapy had nearly 12 months longer median survival 
compared to the other 3 groups: 17.9 months vs. 5.7 months (severe pain but low opioid 
requirement), 6.5 months (low pain but high opioid requirement), and 6.2 months (severe pain 
and high opioid requirement), log-rank p = 0.002. In multivariable models, longer survival in 
the LPLO group was sustained after adjustment for known prognostic factors including age, 
stage and performance status. In various malignancies, at least 3 prospective studies suggest that 
endogenous or pharmacological opioids may promote cancer progression in patients with 
astrocytomas,45 pancreatic cancer46 and various advanced solid tumors.47  
More recently, we found that opioid exposure during the first 3 months after first treatment in 
1,386 patients with stage IV non-hematologic malignancies (largest subgroup [~ 40%] lung 
cancer) was independently predictive of overall survival (P < 0.0001).48 
Several additional retrospective clinical studies from our group and others have reported that (1) 
human lung cancers express opioid receptors,3 (2) opioid receptor expression is greater in 
metastatic lesions compared to the primary tumor,49 and (3) opioid exposure is associated with 
tumor progression/recurrence and shorter survival.50,51  
Importantly, a recent study showed that administration of a PAMORA to patients with advanced 
malignancies was associated with a significantly lower rate of tumor progression compared to 
placebo (13.8% vs 25.4% respectively; P = 0.03).52  
Further, pain itself increases the levels of circulating endogenous opioids (e.g. endorphins). It is 
therefore possible that even in patients who are not receiving pharmacological opioid 
medications, elevated levels of endogenous opioids may themselves activate peripheral MORs 
and cross-activate signaling pathways that influence tumor progression. This mechanism may 
be responsible for the known adverse prognostic effect of pain in malignancies including 
prostate cancer,53-57 NSCLC58 and other malignancies.59  


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The above observations raise the possibility that inhibiting the activity of opioids on peripheral 
opioid receptors by a PAMORA medication may improve HRQoL by mitigating both the 
symptoms related to tumor progression and the peripheral adverse effects of opioids.  
 
Figure 1 
 
 
 
Panels from Fig. 1 in Belani et al. 2012,10 showing the time to worsening (TWS) of pain and 
overall quality of life (QoL) in patients with advanced NSCLC receiving maintenance 
pemetrexed (blue/lighter lines) or placebo (red/darker lines). In these figures, TWS is shown 
from the date of randomization to maintenance pemetrexed or placebo. Randomization to 
maintenance was preceded by platinum-based induction chemotherapy given over 
approximately 3 months. 
TWS for pain occurred at a median of 6.1 (95% CI: 4.6 – 9.6) months and TWS for overall QoL 
occurred at a median of 5.8 (95% CI: 4.4 – 8.4) months in patients receiving maintenance 
pemetrexed. The corresponding durations were 4.6 (95% CI: 3.3 – 6.0) and 3.7 (3.0 – 5.5) 
months respectively in patients on the placebo arm who did not receive maintenance 
pemetrexed. 
1.8 
Naloxegol and other PAMORAs 
Clinically, PAMORAs are well known to ameliorate opioid-induced constipation mediated by 
peripheral opioid receptors, without compromising the analgesic effect of opioids mediated by 
central opioid receptors.13 In short-term studies in healthy volunteers, these drugs also reduce 
morphine-induced peripheral adverse effects including nausea, pruritis and flushing, as well as 
a composite score of these and other adverse effects.25,26 The PAMORA methylnaltrexone is 
effective in relieving opioid-induced constipation in terminally ill patients with diverse 
advanced malignancies, and intermediate-term (up to 4 months) administration is well tolerated 
without inducing opioid withdrawal or worsening of pain.61,62 A recent post-hoc analysis 
suggests that PAMORAs may also ameliorate tumor progression in humans.52  
Of the PAMORAs, naloxegol (PEGylated naloxone; Movantik®) is the only oral agent 
approved by the FDA for prolonged treatment of opioid-induced constipation in non-cancer 
patients.27 Naloxegol needs to be administered only once a day by mouth, does not adversely 
affect the analgesic effects of opioids, and is generally well tolerated with adverse effects largely 


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limited to mild-moderate and transient gastrointestinal symptoms.27,28 It has been administered 
in long-term studies in 537 patients for ≥ 6 months and in 320 patients for ≥ 12 months.28 
Importantly, naloxegol does not influence cardiac repolarization or prolong the QTc interval.63 
Adverse events leading to discontinuation of naloxegol occurred in 10.5% of 804 non-cancer 
patients in a long-term (52 week) study, primarily due to gastrointestinal events (diarrhea, 
abdominal pain, nausea/vomiting).64  It does not carry a risk for dependency/abuse and has 
recently been determined to not be a controlled substance.65 Thus, what is known about 
naloxegol is that: (a) It is an orally administered PAMORA that inhibits peripheral opioid 
receptors, and (b) It is safe and effective in relieving opioid-induced constipation in non-cancer 
patients. 
1.9 
 Study Hypotheses  
Primary hypothesis: Long-term administration of naloxegol is feasible and safe in patients 
receiving first line systemic therapy for advanced malignancy (NSCLC). 
Secondary hypothesis: Activation of peripheral opioid receptors promotes cancer progression 
and mediates the distressing side effects of opioid medications, together leading to worsening 
of disease-related symptoms and impairment of HRQoL. Selective inhibition of peripheral 
opioid receptors will improve HRQoL by ameliorating both these undesirable effects of opioid 
receptor activation (tumor progression and peripheral adverse effects), without compromising 
analgesia (which is mediated by central opioid receptors, i.e. in the CNS). 
1.10 
How this pilot study will provide essential data for a future, more definitive study, and its 
possible design: 
Information that needs to be generated from the currently proposed pilot study in order to 
proceed to a phase II or III trial: (a) best dose of naloxegol to use, (b) tolerability/safety and 
feasibility information, (c) ideally, suggestions of efficacy pertaining to HRQoL (from inhibition 
of tumor progression and amelioration of opioid peripheral adverse effects).  
(a) It is possible that the optimal dose of naloxegol for relieving constipation may be different 
from the dose that effectively inhibits opioid receptors in advanced NSCLC. If both FDA-
approved doses of naloxegol induce an equally significant beneficial effect, we will choose the 
lower (12.5 mg/day) dose for a subsequent study. If the higher dose (25 mg/day) demonstrates 
greater efficacy without causing a significant increase in toxicity, we will select that dose.  
(b) Since this will be a pilot study of a relatively recently approved medication, we chose to 
include a co-primary endpoint of safety and feasibility. Acceptable levels of the feasibility 
endpoints (accrual rate ≥ 80% of target and ≥ 80% of patients alive at 6 months remaining on 
study for at least 6 months) are specified in the study design (below). The duration of treatment 
with the study drug/placebo will be 2 years, since the primary endpoints will be reached by this 
time and because this period will be beyond the expected median survival of 13-17 months for 
the study population. 
(c) Naloxegol is likely to influence HRQoL by reducing the adverse peripheral effects of 
opioid analgesics, particularly constipation, and perhaps nausea, vomiting or other adverse 
effects. We therefore expect that physical well-being and functional well-being will be most 
likely to be improved by use of this drug. HRQoL may be further improved if tumor progression 
is slowed, and therefore all aspects of HRQoL could be positively affected. In this study, we 
therefore want to observe that administration of naloxegol is associated with a generally 
accepted magnitude of clinically meaningful improvement (change in TOI score at 6 months11; 
FACT-L; Appendix VI) that naloxegol improves HRQoL items listed in Appendix V (e.g. dry 
mouth, urinary symptoms, increased sweating, or vomiting etc.,) more than placebo, and that 
naloxegol results in less constipation than placebo (Appendix III).  


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The design of a future phase II or III study will largely depend on the above aspects. Endpoints 
of major importance for such larger, definitive studies will include HRQoL, PFS, OS, and safety 
profile.  
2.0 
OBJECTIVES  
2.1 
Primary objective  
To determine feasibility and safety of long-term administration of two doses of a peripheral opioid 
receptor antagonist in patients with advanced NSCLC receiving first-line systemic therapy. 
2.2 
Secondary objective(s) 
2.2.1 
To explore whether patients randomized to one or both of the two study drug arms have 
less decline in HRQoL than patients randomized to placebo. 
2.2.2 
To estimate the difference in the pain levels and opioid/non-opioid analgesic requirements 
between patients receiving naloxegol or placebo. 
2.2.3 
To estimate the difference in the adverse peripheral effects of opioids (e.g. constipation, 
nausea/emesis, dry mouth and urinary retention) between patients receiving naloxegol or 
placebo. 
2.2.4 
To explore whether there is a signal that naloxegol may be associated with longer PFS and 
OS. 
2.2.5 
To evaluate the difference in discontinuation rate of systemic therapy due to AEs and 
deaths attributable to systemic therapy. 
2.3 
Correlative science objective 
2.3.1 
To examine if MOR expression or activation is a prognostic marker in advanced NSCLC, 
and whether its expression/activation can be used to guide pain management. (Specific 
biomarkers to be examined are listed in Section 14.1.3)   
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers 
or cervical carcinoma in situ. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and are free of disease for ≥ 3 years. 


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• 
Patients who cannot swallow oral formulations of the agent(s). 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method of 
birth control throughout their participation in this study due to the teratogenic potential of 
the therapy utilized in this trial. Appropriate methods of birth control include abstinence, 
oral contraceptives, implantable hormonal contraceptives or double barrier method 
(diaphragm plus condom). Women of childbearing potential must use two forms of barrier 
contraception for the duration of the study and for 12 weeks (3 months) post-treatment. 
Sexually active male patients must use a double-barrier contraception (condom with 
spermicide) from the first dose of study drug until (12 weeks) after the last dose. Women of 
childbearing potential must have a negative pregnancy test ≤ 7 days prior to registration. 
Concurrent enrollment to therapeutic clinical trials: In general, per Alliance policies, 
concurrent registration to other clinical trials using investigational treatments is not allowed. 
However, for this study concurrent registration on other lung cancer trials is allowed, provided 
the patient meets all eligibility criteria listed in Section 3.2. Contact the Alliance A221504 Study 
Chair and Protocol Coordinator to verify that concurrent enrollment is appropriate for the 
patient. 
3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 
3.2.1 
Documentation of Disease:  
Histologic Documentation: Advanced (stage IIIB or IV) non-small cell lung 
cancer diagnosed by biopsy of the primary or metastatic site. (AJCC 7.0.92) 
___ 
3.2.2 
No known presence of known EGFR or EML4-ALK driver mutations in the 
tumor. 
___ 
3.2.3  Started first-line systemic therapy of the investigator’s choice within 12 weeks 
prior to registration,  or planning to initiate first-line systemic therapy of the 
investigator’s choice within 4 weeks after registration. No planned initiation of 
definitive (potentially curative) concurrent chemo-radiation. 
___ 
3.2.4 
No prior systemic therapy for advanced NSCLC, including chemotherapy, 
targeted therapy or immunotherapy (other than current treatment). Prior 
palliative radiation permitted; prior adjuvant systemic therapy /radiation is 
permitted. 
___ 
3.2.5  No more than 7 days of prior use of mixed opioid agonist/opioid antagonists 
or other opioid antagonists within 4 weeks before registration (See list of 
drugs in section 7.3). Patients should not receive such medications after 
registration and for the entire duration of study treatment.  
___ 
3.2.6 
No methadone within 4 weeks prior to registration. 


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___ 
3.2.7 
Patients must have used opioid medication(s) for pain at some time in the 4 
weeks prior to registration.  Current use of opioids (at the time of registration) 
and/or later during the course of the study is permitted but not required. 
___ 
3.2.8 
Expected survival > 3 months. 
___ 
3.2.9 
No concurrently active second invasive malignancies except non-melanoma 
skin cancer. (See Section 3.1 for definitions). 
___ 
3.2.10 No history of gastrointestinal obstruction, or conditions that increase the risk 
of gastrointestinal obstruction, perforation, bleeding or impairment of the 
gastrointestinal wall. No abdominal surgery within 60 days of registration. 
___ 
3.2.11 No acute gastrointestinal conditions, such as: obstruction, fecal impaction, 
obstipation, acute surgical abdomen, ongoing need for manual maneuvers to 
induce bowel movements (such as digital evacuation). 
___ 
3.2.12 No conditions that may compromise blood-brain barrier permeability (e.g., 
multiple sclerosis, recent brain trauma, Alzheimer’s disease, or uncontrolled 
seizures).  
• 
No symptomatic and untreated brain metastases. Patients will be eligible for 
study if radiation therapy for brain metastases was completed at least 7 days 
prior to registration. 
• 
Patients having received stereotactic radiation will be eligible if the radiation 
was completed at least 7 days prior to registration. 
• 
Patients having undergone surgical resection of brain metastases will be 
eligible after they have healed and recovered from the surgical intervention 
sufficiently to start systemic treatment for NSCLC, as determined by a 
neurosurgeon. 
• 
No known leptomeningeal carcinomatosis. 
___ 
3.2.13 No history of myocardial infarction ≤ 6 months prior to registration. No 
current symptomatic congestive heart failure, uncontrolled angina or 
uncontrolled cardiac arrhythmias. 
___ 
3.2.14 No severe hepatic impairment (Child-Pugh class C) or acute liver disease. 
___ 
3.2.15 No known serious or severe hypersensitivity reaction to naloxegol or any of 
its excipients. See list of excipients in Section 10.1. 
___ 
3.2.16 No concurrent use of moderate/strong CYP3A4 inhibitors, or strong CYP3A4 
inducers. (See Sections 8.1.5 and 8.1.6) 
___ 
3.2.17 Not pregnant and not nursing, because this study involves an investigational 
agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus 
and newborn are unknown. 
Therefore, for women of childbearing potential only, a negative pregnancy 
test done ≤ 7 days prior to registration is required. A female of childbearing 
potential is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive months (i.e., has had menses at any time in the preceding 12 
consecutive months). 


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___ 
3.2.18 Age ≥ 18 years  
___ 
3.2.19 ECOG Performance Status 0-2 
___ 
3.2.20 Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Calc. Creatinine Clearance 
≥ 60 mL/min * 
Total Bilirubin 
≤ 1.2 x upper limit of normal (ULN)** 
AST and ALT  
≤ 2.5 x upper limit of normal (ULN) 
 
* Calculated using the Cockcroft-Gault formula 
             **Unless due to Gilbert’s disease 
 
 






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4.2.1 
Additional site registration requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
PO on the protocol.  
• 
Log on to the CTSU members’ website 
using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of your screen 
- 
Enter the protocol number in the search field at the top of the protocol tree, or 
- 
Click on the By Lead Organization folder to expand, then select Alliance, and 
protocol number [A221504]. 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.) 
4.2.3 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website  
Regulatory  Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 
 in order to 
receive further instruction and support. 
4.2.4 
Checking Your Site’s Registration Status  
You can verify your site’s registration status on the members’ side of the CTSU website.  
• 
Log on to the CTSU members’ website; 
• 
Click on Regulatory  at the top of your screen; 
• 
Click on Site Registration;  
• 
Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol requirements 
for individuals participating on the protocol or the enrolling investigator’s status with the 
NCI or their affiliated networks. 






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5.0 
STUDY CALENDAR 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
Pre-Study Testing Intervals  
• 
To be completed ≤ 7 DAYS before registration: Pregnancy test. 
• 
To be completed ≤ 14 DAYS before registration: All laboratory studies, history and physical. 
• 
 
Prior to 
Registration 
Prior to the 
start of 
treatment* 
Every 6 weeks (+/- 7 
days) until 1 year after 
start of treatment** 
Every 3 months (+/- 7 days) 
from 1 year to 2 years after 
the start of treatment 
Tests & Observations 
 
 
 
 
History and physical, weight, PS 
X (1) 
 
 
 
Adverse Event Assessment 
 
X 
A 
X 
PRO-CTCAE (Appendix V) 
 
X 
B 
X 
Urinary Hesitancy Question (Appdx V) 
 
X 
B 
X 
FACT-L (Appendix VI) 
 
X 
X (3) 
X 
Bowel Function Diary (Appendix IV) 
 
X 
B 
X 
Pain and Pain Med Diary (Appdx I) 
 
X 
B 
X 
Patient Medication Diary (See Appdx II) 
 
 
X (4) 
X (4) 
Laboratory Studies 
 
 
 
 
Complete Blood Count, Differential 
X 
X 
C 
 
Serum/plasma Creatinine  
X 
X 
C 
 
AST, ALT, Alk. Phos., total bilirubin 
X 
X 
C 
 
Sodium and potassium 
X 
X 
C 
 
Serum or Urine HCG 
X (2) 
 
 
 
Correlative studies: For patients who consent to participate 
Tissue  
(see Section 6.2) 
Blood sample 
(see Section 6.2) 
* 
Labs completed prior to registration may be used for prior to the start of treatment tests if obtained ≤ 14 days 
prior to treatment.  
** 
While it is expected that patients will visit the clinic at least every 6 weeks, the cycle length for reporting 
treatment and adverse events is every 3 weeks. 
1 
The history and physical exam should specifically include information regarding smoking status, weight loss, 
stage of lung cancer, and presence/absence of known brain metastases. 
2 
For women of childbearing potential (see Section 3.3). Must be done ≤ 7 days prior to registration.  
3 
To be collected on Weeks 3 and 6 (Cycles 1 and 2), then every 6 weeks (i.e., Week 12/Cycle 4, Week 18/Cycle 
6, Week 24/Cycle 8, etc.). 
4 
To be provided to patients for site and patient convenience only. 
A 
Every 3 weeks. For patients who are not scheduled to visit the clinic every 3 weeks, adverse event assessment 
should be done by telephone. 
B 
Every 3 weeks. For patients who are not scheduled to visit the clinic every 3 weeks, booklets may be given to 
the patient to complete at home and return to the clinic by mail or at the next clinic visit. 
C 
To be collected on Weeks 3 and 6 only. 




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should be instructed to return the booklets to site staff either in person or by mail and site 
staff will enter patient and caregiver responses into Rave.  
6.1.3 
Supporting documentation 
This study requires supporting documentation for diagnosis, anti-cancer treatment 
administered (systemic therapy and/or radiation), response, progression and survival. 
Supporting documentation will include pathology and radiology reports and must be 
submitted at the following time points: 
Baseline: Pathology and radiology reports and clinic notes 
At Progression and response: Radiology reports and clinic notes, based on standard 
RECIST criteria.   
All supporting documentation should be de-identified according to institutional standards 
prior to upload into RAVE.  
6.1.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
 
 


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6.2 
Specimen collection and submission  
For patients registered to substudy A221504-ST1: All participating institutions must ask patients 
for their consent to participate in the correlative sub-studies planned for Alliance A221504-ST1, 
although patient participation is optional. Biomarker studies will be performed. Rationale and 
methods for the scientific components of these studies are described in Section 14.0. For patients 
who consent to participate, tissue and blood will be collected at the following time points for 
these studies: 
 
At 
Registration 
3 weeks  
(+/-7 days)  
after start of 
study 
medication 
6 weeks  
(+/-7 days)  
after start of 
study 
medication 
Storage/ 
Shipping 
conditions  
Submit to: 
For patients registered to A221504-ST1, submit the following: (optional) 
Diagnostic tumor  
tissue block  
(biopsy or surgery) (1) 
X 
 
 
Ambient 
Alliance 
Biorepository 
at Mayo Clinic 
FFPE Tissue 
Number and volume of tubes to draw 
Whole blood (2) 
(EDTA/lavender top) 
(see Section 6.2.3) 
1 x 5 mL 
1 x 5 mL 
1 x 5 mL 
pack/ship 
plasma on 
dry ice 
over night 
Alliance 
Biorepository 
at Mayo Clinic 
BAP Freezer 
Whole blood (2) 
(Heparin/green top) (see 
Section 6.2.3) 
1 x 5 mL 
1 x 5 mL 
1 x 5 mL 
pack/ship 
plasma on 
dry ice 
over night 
Alliance 
Biorepository 
at Mayo Clinic 
BAP Freezer 
(1) Tissue to be used for biomarker analyses described in Section 14.1. See Section 6.2.2 for 
alternative submission.  
(2) Plasma from whole blood to be used for biomarker analyses described in Section 14.1. See 
Section 6.2.3 for processing instructions and Appendix VIII.  
6.2.1 
Specimen submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL:  
 using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please refer 
to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, and 
training videos.  To report technical problems, such as login issues or application errors, 
please contact: 
 For assistance in using the 
application or questions or problems related to specific specimen logging, please contact: 
 
Sample collection kits must be ordered thought BIOMS.  Please log into BioMS, and click 
on “Kit Requests” to order blood specimen kits. 


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After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A221504), Alliance 
patient number, patient’s initials, date and type of specimen collected (e.g., serum, whole 
blood). See Section 6.2.2. 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Ship specimens on Monday through Friday only. Shipping by overnight service to assure 
receipt is encouraged.  
6.2.2 
Collection and Submission of Diagnostic Tumor Tissue 
For patients who consent to participate, tumor blocks will be used for the analyses described 
in Section 14.1. 
Paraffin blocks of diagnostic tumor tissue (from primary or metastatic site) should be sent 
to the Alliance Biorepository at Mayo Clinic FFPE Tissue.  
The Alliance has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block. If, due to institutional policy, a block cannot 
be sent then please send slides of diagnostic tumor tissue.  
The goal of the Alliance Biorepository is to provide investigators with quality histology 
sections for their research while maintaining the integrity of the tissue. For these reasons it 
is preferred that the Alliance Biorepository bank the block until the study investigator 
requests thin sections. Please contact the Alliance Biorepository if additional assurances 
with your hospital pathology department are required. 
If an institution is unable to provide a tissue block, please submit either of the 
following:  
10 unstained PLUS-charged glass slides (or as many as possible if fewer than 10) of 4-6 
micron thick sections from: 
• 
The most recent diagnostic biopsy confirming advanced (stage IIIB/IV) non-small cell 
carcinoma of the lung OR 
• 
A diagnostic biopsy (or surgery) performed previously, if the patient was previously 
diagnosed and/or treated for the same malignancy (i.e., early stage non-small cell 
carcinoma of the lung) and has now progressed or relapsed OR 
• 
A fine needle aspiration (FNA) or cell block, if only a FNA or bronchoscopic washings 
were performed (or found to contain diagnostic material). 
Label the unstained slides with Alliance patient ID number, accession number, and 
order of sections via institution’s standard method for labeling clinical slides or using a 
permanent marker. Please DO NOT use sticky labels. 
Tissue sample should be sent within 7 days after registration. A de-identified surgical 
pathology report should be sent with tumor tissues (blocks or unstained slides). Usually, this 
is generated by obscuring all PHI (names and dates) with white-out or a black magic marker, 
labeling each page of the report with the Alliance patient ID, and photocopying the report. 






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Patients will discontinue all maintenance laxatives/stool softeners/fiber therapy the day (at least 
24 hours) prior to initiation of naloxegol/placebo. Laxatives/stool softeners/fiber can be restarted 
and used as needed if constipation persists for three or more days after starting 
naloxegol/placebo.  
Advanced lung cancer is considered to be incurable, and patients with progressive disease often 
experience increasing pain that requires treatment with escalating doses of opioids. Since the 
objective of this study is to examine whether naloxegol can mitigate the adverse effects of 
opioids, the study drug should be continued for as long as possible for up to 2 years.  
Recommendations for missed doses:  If a patient vomits, there is a possibility that some of the 
dose may already have been absorbed. Another dose must NOT be administered the same day. 
The patient should take the following day’s dose at the correct time on the next day. 
Similarly, if a patient has forgotten a dose, it may be reasonable for them to take it if only a few 
hours have elapsed since the scheduled time, but skip that day’s dose if it has been many hours. 
7.2 
First-line systemic therapy. 
The choice of first-line systemic therapy, number of cycles to be administered, and whether or 
not maintenance treatment is used, will be at the discretion of the treating physician. Systemic 
therapy may include chemotherapy with/without immunotherapy (e.g. pembrolizumab) or anti-
angiogenic agents (e.g. bevacizumab), immunotherapy alone, or other agents. 
7.3 
Opioids 
The use of standard opioids (and other analgesics) to control pain adequately will be permitted 
at the discretion of the treating physician.  
While patients are receiving naloxegol/placebo, the use of mixed opioid agonists/antagonists or 
other opioid antagonists will not be permitted (e.g. pentazocine, buprenorphine, nalbuphine, 
naloxone and other naloxone containing products such as oxycodone/naloxone combinations 
[e.g., 
Targin®], 
naltrexone 
and 
other 
naltrexone 
containing 
products 
such 
as 
morphine/naltrexone combinations [e.g., Embeda®], methylnaltrexone [Relistor®], or 
alvimopan [Entereg®]). Patients who have used such drugs in the past will not be eligible for 
this study. 
Additionally, since patients receiving methadone may experience a higher frequency of GI 
adverse effects possibly related to opioid withdrawal upon administration of naloxegol, the use 
of methadone while patients are receiving naloxegol/placebo will not be permitted. Patients 
who have used methadone in the past 4 weeks prior to registration will not be eligible for this 
study. 
8.0 
DOSE AND TREATMENT MODIFICATIONS & UNBLINDING  
8.1 
Ancillary therapy, concomitant medications, and supportive care 
Use of mixed opioid agonists/antagonists or other peripheral opioid antagonists will not be 
permitted as long as patients are taking the study medication/placebo on this trial. 
Administration of standard opioids and other analgesics to control pain adequately will be 
permitted at the discretion of the treating physician. Pain levels and actual opioid and non-
opioid analgesic use will be recorded using patient diaries.  
8.1.1 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions. All blood products and concomitant medications such as 


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antidiarrheals, analgesics, and/or antiemetics received while on naloxegol/placebo will be 
recorded in the medical records. 
8.1.2 
Antiemetics, including aprepitant or fosaprepitant, may be used at the discretion of 
the treating physician. 
8.1.3 
Diarrhea management is per the discretion of the treating physician. Diarrhea could 
be managed conservatively with medications such as loperamide. 
Patients with severe diarrhea should be assessed for intravenous hydration and correction of 
electrolyte imbalances. 
8.1.4 
Palliative radiation therapy may be administered at any time as needed, including 
whole-brain and/or stereotactic irradiation given for documented CNS disease. 
Continue protocol treatment (naloxegol or placebo) during irradiation.  
8.1.5 
CYP3A4 Inhibitors 
Chronic concomitant treatment with moderate or strong inhibitors of CYP3A4 is not 
allowed during this trial. The following drugs are EXAMPLES of strong inhibitors of 
CYP3A4 and are not allowed during treatment with naloxegol. 
• 
Indinavir 
• 
Clarithromycin 
• 
Ketoconazole 
• 
Cannabinoids 
 
The following drugs are EXAMPLES of moderate inhibitors of CYP3A4 and are not 
allowed during treatment with naloxegol*: 
• 
Diltiazem 
• 
Erythromycin 
• 
Verapamill 
• 
Grapefruit juice 
• 
Fluconazole 
Because lists of these agents are constantly changing, please consult an updated list and 
review any drugs being taken by the patients for their potential to inhibit CYP3A4. 
Examples of resources that may be utilized include the product information for the 
individual concomitant drug in question, medical reference texts such as the Physicians’ 
Desk Reference, the FDA website, or your local institution’s pharmacist. 
* 
While Aprepitant is a moderate inhibitor of CYP3A4 its short-term use (up to 3 days) 
as an antiemetic with each cycle of chemotherapy will be allowed. 
 
 


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8.1.6 
CYP3A4 Inducers 
Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed during this 
trial. The following drugs are EXAMPLES of strong inducers of CYP3A4 and are not 
allowed during treatment with naloxegol. 
• 
Rifampin 
• 
Carbamazepine 
Because lists of these agents are constantly changing, please consult and review any drugs 
for their potential to induce CYP3A4. Examples of resources that may be utilized include 
the product information for the individual concomitant drug in question, medical reference 
texts such as the Physicians’ Desk Reference, the FDA website, or your local institution’s 
pharmacist. 
8.2 
Dose Modifications 
CTEP-AERS reporting may be required for some adverse events (See Section 9.0). PRO-
CTCAE data should not be used for determining dose modifications.  
8.2.1 
Abdominal Pain 
If patients develop unusually severe, persistent or worsening ≥ grade 2 abdominal pain or 
other symptoms/signs of GI perforation or obstruction, naloxegol/placebo will be 
temporarily held and patients will be advised to obtain urgent medical attention.  
8.2.2 
Hepatotoxicity 
For grade 2 or higher (ALT or AST > 3 x ULN) hepatotoxicity, patients will be evaluated 
clinically. 
Naloxegol/placebo will be temporarily held for patients who develop any of the following: 
• Grade 2 ALT or AST > 3-5 x ULN AND any of the following: 
Grade 2 or higher total bilirubin (> 1.5 x ULN) 
Grade 2 or higher INR (> 1.5)  
Symptoms including fatigue, nausea, vomiting, right upper quadrant 
pain/tenderness, fever, rash, and/or eosinophilia. 
• Grade 3 or higher ALT or AST (> 5 x ULN)  
 
Naloxegol/placebo may be resumed for patients who recover to ≤ grade 2 ALT or AST (≤ 5 
x ULN), ≤ grade 1 bilirubin and INR, and have no symptoms or signs of liver dysfunction. 
All patients developing liver dysfunction should be monitored clinically and with serial 
laboratory tests, as clinically appropriate. 
8.2.3  Diarrhea, nausea or vomiting 
An assessment of whether these symptoms are related to systemic therapy or to 
naloxegol/placebo must be made.  
For grade 2 or higher nausea, vomiting or diarrhea, believed to be at least possibly 
related to the study drug, naloxegol/placebo will be held temporarily. Naloxegol/placebo 
may be resumed with the original treatment schedule once these symptoms have improved 
to grade 1 or better.  
At the treating physician’s discretion, anti-diarrheal and anti-emetics can be used 
prophylactically to prevent another episode of grade 2-4 symptoms. If grade 2 or higher 


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nausea, vomiting or diarrhea believed to be at least possibly related to naloxegol/placebo 
recurs, then naloxegol/placebo will be permanently discontinued. 
8.2.4 
Other adverse events 
Naloxegol/placebo will be temporarily held for any hematological or non-hematological 
toxicity believed to be possibly/probably/definitely related to the study drug and grade 2-4 
in severity. Naloxegol/placebo will be resumed with the original treatment schedule once 
toxicity has improved to grade ≤ 1. If toxicity of grade 2-4 recurs, the naloxegol/placebo 
will be permanently discontinued. 
Patients will be taken off protocol treatment if they are unable to resume naloxegol/placebo 
for ≥ 4 weeks because of persistent grade 2-4 toxicity that is possibly/probably/definitely 
related to the study drug/placebo.  
If patients develop symptomatic brain metastases during the study (while patients are taking 
the study drug), it will be recommended that the study drug be temporarily withheld until 7 
days after the end of radiation therapy, or until after recovery from brain surgery/resection 
of brain metastases. 
If patients develop leptomeningeal carcinomatosis during the study, the study drug will be 
discontinued permanently. 
8.2.5 
Pregnancy: Naloxegol/placebo will be discontinued immediately and permanently for any 
patient who becomes pregnant during the treatment period of the study. 
8.2.6 
Chemotherapy 
Dose adjustments and cycle delays for the individual chemotherapeutic agents used will be 
per institutional guidelines/practice and the package inserts. 
8.3 
Unblinding Procedures 
Unblinding can be done only in cases of an emergency. Follow the directions below to unblind 
patient treatment. Please note that if a treatment assignment is unblinded, the patient must 
discontinue protocol therapy. 
Emergency Unblinding Procedures: 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at least 
possibly related to the investigational agent and for which unblinding would influence treatment 
decisions; or 2) medication error, such as accidental overdose. Expected adverse events are listed 
in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 773-702-6800, pressing 1 to speak 
with an operator, and then asking for pager ID 8625 to return the call.  
The institution must provide the following information to the Alliance Executive Officer: 
• 
Alliance study ID (i.e., “A221504”) 
 
• 
Alliance patient ID number (e.g., “999999”) 
• 
Patient initials (e.g., “L, FM”) 
• 
Institution name 
• 
Name and telephone number of treating physician 
• 
Name and contact information of person requesting the unblinding procedure 
• 
Name and contact information of person to inform of treatment assignment 
• 
Reason for emergency unblinding 


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Please remember that an emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. 
After the Executive Officer deems unblinding is warranted, the treatment assignment will be 
provided to the contact person at the treating site. 
Procedures for unblinding after completion of treatment with naloxegol/placebo 
Study participants can be unblinded after 2 years of treatment with naloxegol/placebo and all 
appropriate study forms have been completed.  
To receive patient treatment assignment in either of these cases, contact the Alliance 
Registration Office at 
 during regular business hours. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0. However, CTCAE v5.0 must be used for serious AE reporting through 
CTEP-AERS 
as 
of 
April 
1, 
2018. 
The 
CTCAE 
is 
available 
at 
. 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures. 
NOTE: PRO-CTCAE data should not be used for determining attribution, or reporting of adverse 
events.  
9.1 
Routine adverse event reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Event Solicited 
form is used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment by CTCAE, PRO-CTCAE, or both.  
 
CTCAE v4.0 Term 
PRO-CTCAE v1.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Abdominal pain 
Abdominal Pain 
Gastrointestinal Disorders 
Headache 
Headache 
Nervous system disorders 
Hyperhidrosis 
Increased Sweating 
Skin and subcutaneous tissue disorders 
Diarrhea 
Diarrhea 
Gastrointestinal Disorders 
Nausea 
Nausea 
Gastrointestinal Disorders 
Flatulence 
Gas 
Gastrointestinal Disorders 
Vomiting 
Vomiting 
Gastrointestinal Disorders 
Gastric perforation 
 
Gastrointestinal Disorders 


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Small intestinal perforation 
 
Gastrointestinal Disorders 
Colonic perforation 
 
Gastrointestinal Disorders 
Rectal perforation 
 
Gastrointestinal Disorders 
Opioid withdrawal 
 
State presence or absence 
Dry mouth 
Dry Mouth 
Gastrointestinal Disorders 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to 
the Alliance Statistics and Data Center. Questions about routine reporting should be directed 
to the Data Manager.  
 
*Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs) 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Alliance Central Protocol 
Operations Program, the Study Chair, and their Institutional Review Board if a patient has a 
reportable serious adverse event. The descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5 will be utilized for AE reporting. 
The 
CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
. 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
PRO-CTCAE data should not be used for determining attribution, or reporting of serious adverse 
events. 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause should be provided. 




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• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 calendar 
days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements  
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse events 
that precipitate hospitalization or prolong an existing hospitalization must be reported via CTEP-
AERS. 
• 
Reporting of cases of secondary AML/MDS is to be done using the NCI/CTEP Secondary 
AML/MDS Report Form. New primary malignancies should be reported using Form Notice of 
New Primary. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
• 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should be reported, i.e. solid 
tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors.  
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported 
via the routine reporting mechanisms outlined in each protocol.  


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Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy).  Second malignancies require ONLY routine reporting unless otherwise 
specified. 
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor pathology, 
history or prior tumors, prior treatment/current treatment including duration, any associated risk 
factors or evidence regarding how long the new malignancy may have been present, when and how 
the new malignancy was detected, molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor, and new malignancy treatment and outcome, if available. 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the package insert. 
• 
CTEP-AERS reports should be submitted electronically. 
Pregnancy loss 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
• 
Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
• 
A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, puerperium 
and perinatal conditions SOC, as currently CTEPAERS recognizes this event as a patient death. 
• 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, 
the Pregnancy Information Form should be completed and submitted, along with any additional 
medical information (form is available on the CTEP website at 
). The 
potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS report. 
10.0 DRUG INFORMATION 
10.1 
Naloxegol (IND Exempt) 
Naloxegol is an FDA approved medication that has recently been removed from the list of 
controlled substances.65 Naloxegol is a PEGylated derivative of the opioid antagonist naloxone. 
Naloxegol contains naloxegol oxalate as the active ingredient. Naloxegol is an antagonist of 
opioid binding at the mu-opioid receptor which functions as a peripherally-acting mu-opioid 
receptor antagonist (PAMORA) in tissues such as the gastrointestinal tract, thereby decreasing 
the constipating effects of opioids. The PEG moiety reduces its passive permeability. It is a 
substrate for the P-glycoprotein transporter (P-gp). Due to reduced permeability and increased 
P-gp mediated efflux across the blood-brain barrier, CNS penetration is negligible. Naloxegol 
therefore does not antagonize centrally mediated opioid analgesia. 
No antidote is known for naloxegol. Dialysis was ineffective as a means of elimination in a 
clinical study in patients with renal failure. Patients who have received an overdose of the study 
drug should be monitored closely for potential evidence of opioid withdrawal symptoms such 
as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Treatment should be 
based on the degree of opioid withdrawal symptoms, including changes in blood pressure and 
heart rate, and on the need for analgesia. 
Procurement 
Naloxegol will be provided by Astra Zeneca and distributed by the Alliance Research Base 
Pharmacy. The pharmacy will deliver patient-specific supplies of 18 tablets per bottle, and 
patients will be provided with a 3 month supply of five bottles containing 12.5 mg tablets and 
another five bottles containing 25 mg tablets at a time. Sites should not repackage bottles 
within the kit, and drug should be dispensed in the original bottles. 




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Patients should avoid consumption of grapefruit or grapefruit juice. 
Drug Interactions 
Concomitant use of naloxegol is not recommended with the following classes of medications: 
Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole [except topical use], 
cyclosporine, indinavir, nelfinavir, ritonavir, itraconazole, verapamil) 
Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil)    
Strong CYP3A4 inducers (e.g., rifampin) 
Opioid antagonists and mixed agonists/antagonists. EXAMPLES of such medications include: 
pentazocine, buprenorphine, nalbuphine, naloxone and other naloxone containing products such 
as oxycodone/naloxone combinations [e.g., Targin®], naltrexone and other naltrexone 
containing 
products 
such 
as 
morphine/naltrexone 
combinations 
[e.g., 
Embeda®], 
methylnaltrexone [Relistor®], or alvimopan [Entereg®]). 
Pharmacokinetics 
Absorption: rapid. With a high fat meal, Cmax and AUC increase by 30% and 45% respectively. 
Distribution: Vd 968-2140 L. 
Protein binding: Low at approximately 4.2%. 
Metabolism: Primarily hepatic via CYP3A4. 
Half-life: 6-11 hours. 
Excretion: primarily fecal (68%, approximately 16% as unchanged drug); urinary (16%, <6% 
as unchanged drug). 
Adverse Events 
 
Warnings/Precautions: 
Gastrointestinal Perforation: Gastrointestinal perforation has been reported with another 
peripherally acting opioid antagonist in patients with conditions associated with compromised 
structural integrity of the gastrointestinal tract wall. Monitor for the development of severe, 
persistent or worsening abdominal pain; discontinue study drug and obtain urgent medical 
evaluation of patients who develop this symptom. 
Opioid Withdrawal: Hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and 
yawning have occurred in patients treated with naloxegol. Patients receiving methadone have a 
higher frequency of gastrointestinal adverse reactions possibly related to opioid withdrawal, 
compared to patients receiving other opioids. Patients having disruptions to the blood-brain 
barrier may be at increased risk for opioid withdrawal or reduced analgesia. Monitor for 
symptoms of opioid withdrawal, particularly in such patients.  
Adverse events: 
>10%: 
GI: Abdominal pain 
 
1%-10%: 
Central Nervous System: Headache 
Dermatologic: Hyperhidrosis 
GI: Diarrhea, nausea, flatulence, vomiting 
 
Table 1 lists adverse reactions in pooled data from clinical studies in non-cancer patients 
receiving naloxegol for opioid-induced constipation, and occurring in ≥ 3% of patients 
receiving 12.5 mg or 25 mg naloxegol and at an incidence greater than placebo.  


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Adverse reaction 
Naloxegol 25 mg  
(n = 446) 
Naloxegol 12.5 mg 
(n = 441) 
Placebo 
(n = 444) 
Abdominal pain 
21% 
12% 
7% 
Diarrhea 
9% 
6% 
5% 
Nausea 
8% 
7% 
5% 
Flatulence 
6% 
3% 
3% 
Vomiting 
5% 
3% 
4% 
Headache 
4% 
4% 
3% 
Hyperhidrosis 
3% 
<1% 
<1% 
 
Nursing Guidelines 
Upon starting the study, the patient and caregiver should be shown the two different 
naloxegol/placebo bottles and different colors of pills with instructions to take one tablet from 
each bottle daily; repeat demonstration from the patient or caretaker is recommended. Patient 
should be reminded to take naloxegol/placebo at least one hour before a meal or at least two 
hours afterwards. Grapefruit and grapefruit juice should be avoided while on naloxegol/placebo.  
The patient medication diary should be explained to the patient and caregiver with instructions 
to note time/date of administration of naloxegol/placebo each day. The level and incidence of 
pain should be noted on the Pain and Pain Medication Diary using a scale of 0-10.  
Patients should be instructed to call the site coordinator whenever a new drug is ordered, 
especially if the provider is outside of the cancer center and not fully aware of the study 
requirements and limitations. In the event of hospital admission, the study coordinator should 
monitor any new drugs to avoid undesirable interactions. 
Patients should be instructed to call the site coordinator with any concerns. Ideally, a 24-hour 
number should be provided to the patient. 
In the event that a 3-week interval visit is missed by the patient, the site coordinator can call the 
patient and obtain responses to the questionnaire(s) items OR discuss mailing the self-reported 
questionnaires with a stamped, returned envelope for return.  
10.2 
Placebo 
A matching placebo will be provided by Astra Zeneca.  It will match the active naloxegol 12.5 
and 25 mg tablets in size, shape and color.  The placebo tablets contain mannitol, 
microcrystalline cellulose and magnesium stearate. The coating material contains hypromellose, 
iron oxide/ferric oxide (red, black and yellow), macrogols/polyethylene glycol and titanium 
dioxide.    
11.0 HEALTH OUTCOMES MEASURES 
Each questionnaire administered in this study is described below. These self-reported questionnaires 
are expected to take less than 15 minutes for completion and be minimally burdensome. In the event 
that the patient is unable to complete the questionnaires, the local study coordinator may help the 
patient. Patients appreciate being asked about their symptoms on such questionnaires, and usually do 
not find them difficult or inconvenient to fill out.74  
11.1 
FACT-L  
The FACT-L75 includes the FACT-G [version 4.0], developed by Cella et al76 as an overall 
cancer-specific HRQoL questionnaire, with a 9-item subscale concerning specific lung cancer 
issues. The FACT-G consists of a self-report 28-item HRQoL measure grouped into four 
subscales: physical well-being (PWB), social/family well-being (SFWB), emotional well-being 


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(EWB), and functional well-being (FWB). Most items are rated on a 5-point Likert scale, from 
0, 'not at all' to 4, 'very much'. When the Lung Cancer Subscale (LCS) is added to FACT-G, 9 
additional items focus on symptoms and issues more specific to lung cancer patients. The FACT-
L will be scored according to the published scoring algorithm and following endpoints computed 
at each time point: FACT-L (PWB + SFWB + EWB + FWB + LCS), Trial Outcome Index (TOI; 
PWB + FWB + LCS), PWB, SFWB, EWB, FWB, and LCS. Higher scores indicate better 
HRQoL. Minimum clinically meaningful change in TOI and LCS scores have been determined11 
and will be used as a guide to assess the effect observed in this trial. See Section 13.0 and 
Appendix VI. 
The focus of the secondary objective is to estimate the difference in HRQoL (TOI, FACT-L) 
improvement at 6 months from baseline between the study drug and placebo. However, 
collecting HRQoL data beyond 6 months (until the end of the 2 year study period) will allow us 
to explore the effect of treatment on long-term HRQoL.  HRQoL data collected beyond 6 months 
will be summarized and compared, using similar methods described for change in HRQoL at 6 
months (See Section 13.4.2). This exploratory analysis may inform the design of future 
randomized long-term studies. 
11.2 
PRO-CTCAEs and urinary hesitancy question 
The standard mechanism for reporting toxicities in cancer research has been clinician-only 
reporting using items from the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAEs). Recently, the NCI has developed a patient-reported version of 
the CTCAE called the Patient-Reported Outcome-CTCAE (PRO-CTCAE). The PRO-CTCAE 
is a library of questions asking patients about specific symptomatic adverse events associated 
with cancer therapy, such as constipation or nausea.  In multiple studies, PRO-CTCAE measures 
have improved the predictive accuracy of clinician CTCAE reporting. In a prospective study 
including lung cancer patients PRO measurements of toxicities better reflected patients’ 
underlying state and functional status than clinicians’ evaluations.77  
For this study, we will use selected PRO-CTCAE items to assess the following symptoms: 
abdominal pain (3 PRO-CTCAE questions), headache (3 PRO-CTCAE questions), 
hyperhidrosis (sweating, 2 PRO-CTCAE questions), diarrhea (1 PRO-CTCAE question), nausea 
(2 PRO-CTCAE questions), flatulence (gas; 1 PRO-CTCAE question), vomiting (2 PRO-
CTCAE questions) and dry mouth (1 PRO-CTCAE question). These items will be included in 
the questionnaires that patients complete at the same time as CTCAE assessments and a urinary 
hesitancy question, every 3 weeks for the first year, then every 3 months during year 2. The 
urinary hesitancy question (a visual analogue scale from 0-10 with 0 representing no symptom 
and 10 representing a symptom as bad as imaginable) is necessary because there are no PRO-
CTCAE items that measure this symptom adequately. Summary statistics will be generated 
regarding change in PRO-CTCAE responses and change in urinary hesitancy scores over time 
in the three arms of the study. See Appendix V.  
11.3 
Bowel function-diary (BF-Diary) 
Constipation will be assessed using modified versions of modules 1 and 2 of the bowel function-
diary (BF-Diary)78 prior to start of treatment and every 3 weeks (+/-7 days). See Section 5.0 and 
Appendix IV. 
11.4 
Pain and analgesic use 
Pain and analgesic use will be assessed via a self-report daily medication/pain diary that patients 
will be asked to complete every day at home and bring to all study-related visits. See Section 
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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
12.1.1 Patients are expected to receive the naloxegol/placebo for up to 2 years, in the absence 
of unacceptable toxicity or withdrawal of consent. Naloxegol/placebo will NOT be 
discontinued for disease progression. After 2 years of protocol treatment, patients may be 
unblinded per Section 8.3 and initiate open-label naloxegol treatment at the discretion of 
the treating physician. 
12.1.2  Discontinuation of study agent:  If the patient discontinues naloxegol/placebo, he/she 
should be followed for disease progression and survival by telephone or clinic visit every 
3 months until 2 years after the date of registration. Submission of QOL booklets after 
discontinuation of naloxegol/placebo is not required. 
12.2 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study patient who is registered to the trial but does not meet all of the eligibility criteria is 
deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study patients who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below.  
Baseline and off-treatment notice data submission required. See the Data Submission Schedule 
accompanying the All Forms Packet. 
12.3 
Extraordinary Medical Circumstances 
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: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Overview 
This is a randomized, double blind, placebo-controlled, three-arm pilot study primarily designed 
to determine the safety and feasibility of the PAMORA naloxegol and to determine the optimal 


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of two FDA-approved doses of the study drug. Patients will be randomized at a 1:1:1 ratio to 
either one of the two doses of naloxegol or placebo.  
13.2 
Sample Size, Accrual Time and Study Duration 
13.2.1 Sample Size 
As this is a pilot study to assess feasibility and safety, it is not powered to test specific 
hypothesis. We plan to enroll a total of 204 patients, 68 patients per arm. Assuming 
approximately 10% of patients will be ineligible due to cancellation or major violations 
leading to a total 184 patients (61 per arm) evaluable for the primary endpoints of feasibility 
and safety. Among patients with advanced NSCLC, 0%, 25% and 33% of those receiving < 
6, 6 – 8, and > 8 cycles discontinued pemetrexed + carboplatin induction chemotherapy for 
toxicity, respectively.79 In phase III studies, deaths attributable to drug toxicity occurred in 
1% and 0.3% patients during the induction and maintenance therapy phases, 
respectively.17,18 About 75% of all patients who start pemetrexed-based chemotherapy for 
NSCLC are expected to be alive at 6 months.17 Thus, we would like to observe that ≥ 80% 
of 75%, corresponding to ≥ 60% of all patients enrolled, continue on naloxegol/placebo for 
at least 6 months (the time point on which the change in Trial Outcome Index (TOI) of the 
FACT-L [secondary endpoint] will also be calculated). We will evaluate the safety of the 
naloxegol/placebo in NSCLC patients receiving systemic therapy by looking at the 
incidence of adverse events according to CTCAE criteria, including potentially expected 
and unexpected toxicities, and study drug vs placebo discontinuation rates, between the 
study arms.  
Although the study is not powered to test specific hypotheses regarding HRQoL, the focus 
of the secondary objective of the study is to estimate the difference in HRQoL improvement 
at 6 months from baseline between the study treatment and placebo. Assuming 75% of 
patients will be alive at 6 months and 80% of these patients will return completed forms, we 
expect 111 patients (37 per arm) to be evaluable for this endpoint. The margin of error of a 
90% two-sided confidence interval with this sample size is .38 SD. Cella et al.11 reported 
that, in patients with advanced NSCLC receiving standard chemotherapy, the minimal 
Clinically Meaningful Change (CMC) size was 5-6 points (effect size, 0.14 – 0.45 SD) on 
the TOI and 2-3 points (effect size, 0.23 – 0.66 SD) on the LCS of the FACT-L, which 
correlated closely with changes in the disease status (objective response vs progression; 
early vs late progression). Using the SD reported in Cella et al.11, the margin of error of .38 
SD is equivalent to a difference of 5.7 points (SD = ~15 points) in TOI and 2 points (SD = 
5 points) in LCS. Therefore, an observed improvement of 5.7 points or higher in TOI (or 2 
points or higher in LCS) in one of the naloxegol arms when compared to the placebo arm 
suggests a benefit in favor of naloxegol. This sample size allows estimation with sufficient 
precision to detect a moderate effect size that falls within the published CMC range.  
13.2.2  Accrual Rate and Accrual Duration 
We anticipate accruing approximately 9 – 10 patients per month, based on our previous 
experience in clinical practice.  This would mean completing the primary accrual within 20 
– 22 months from study initiation. 
13.2.3 Primary Endpoint Completion Date for ClinicalTrials.gov Reporting 
For purpose of ClinicalTrial.gov reporting, the Primary Endpoint Completion Date (PECD) 
for this study is the time the last patient registered has been followed for at least one day. 


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13.3 
Statistical Design and Analysis for the Primary Endpoint 
13.3.1 Primary Endpoint 
The primary endpoint of this study is feasibility and safety which will be evaluated by the 
following criteria:  
(a) The rate of accrual remaining ≥ 80% of the expected (thus ≥ 147 patients by 2 years),  
(b) ≥ 80% of patients who remain alive at 6 months continuing on the study medication, and 
completing the HRQoL and other forms, for at least 6 months, and  
(c) The study continuing without meeting toxicity stopping criteria as specified in Section 
13.5.1.  
13.3.2 Statistical Design 
This is a three-arm parallel group design with neither cross-over nor interim analysis. 
13.3.3 Analysis Plan for the Primary Endpoint 
The criteria for safety and feasibility will be evaluated as described below: 
(a) The observed accrual rate will be calculated as the total number of patients accrued to 
the study over two years divided by 184, the total expected accrual of patients evaluable 
for the primary endpoint,    
(b) The proportion of patients alive at 6 months who continue study drug and complete the 
HRQoL and other forms for at least 6 months will be calculated by arm, and 
(c) The frequency of adverse events will be summarized by arm and compared between each 
treatment arm vs the placebo arm using Fisher’s exact test. 
13.4  Supplementary Analysis Plans 
13.4.1 Secondary and Correlative Endpoints 
1) The change from baseline to 6 months in trial outcome index (TOI), function subscales, 
and lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung 
(FACT-L)  
2) Patient-reported outcome assessed by PRO-CTCAEs and a urinary hesitancy question 
3) The Bowel Function-Diary (BF-Diary) 
4) The level of pain and analgesic use 
5) Unexpected clinical outcomes with systemic therapy 
6) Progression-free survival 
7) Overall survival 
8) Prognostic effect of MOR expression/interaction on HRQoL  
13.4.2 Secondary and Correlative Endpoint Analysis 
1) Descriptive statistics and statistical plots will form the foundation of statistical analysis 
for this endpoint. HRQoL scores at each timepoint and changes in scores between 6 months 
and baseline will be summarized by mean (SD), median (inter-quartile range). Scores will 
be plotted to explore the pattern over time and to examine differences between treatment 
arms. Differences in HRQoL between the treatment arms and the placebo arm will be 
conducted through linear mixed models and growth curve models to account for repeated 
assessments. The model will adjust for baseline LCS and TOI, ECOG performance status, 


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and primary symptoms of advanced NSCLC (≤ 1 vs > 1 symptom) at enrollment. Because 
of exploratory nature, we will not adjust for multiple comparisons. The frequency and 
pattern of missing data will be summarized descriptively and sensitivity analyses will only 
be performed if the overall missing rate is more than 10% and most missing data are deemed 
not at random. Sensitivity analyses are composed of simple imputation, multiple 
imputations, and pattern mixture models and selection models. 
HRQoL data beyond 6 months (until the end of the 2 year study period) will allow us to 
explore the effect of treatment on long-term HRQoL.  HRQoL data collected beyond 6 
months will be summarized and compared, using similar methods described for change in 
HRQoL at 6 months. This exploratory analysis may inform the design of future randomized 
long-term studies. 
2) PRO-CTCAE and Urinary hesitancy items will be summarized by arm. PRO-CTCAE 
response will be compared between the treatment arms vs. placebo arm using a chi-square 
test or Fisher’s exact test as appropriate. PRO-CTCAE and CTCAE data will be presented 
descriptively over time.  Urinary hesitancy scores will be compared between treatment arms 
vs. placebo arm using Wilcoxon test.  
3) OIC rating scale will be summarized by arm. Scores will be compared between treatment 
arms vs. placebo arm using Wilcoxon test. 
4) Pain scores and analgesic use will be summarized by arm. Pain scores will be compared 
between treatment arms vs. placebo using Wilcoxon test. Frequencies of analgesic used will 
be compared using chi-square test or Fisher’s exact test, as appropriate. 
5) Frequency of discontinuation of systemic therapy will be summarized by arm and 
compared between each treatment arm vs the placebo arm using Fisher’s exact test. 
6) The event for PFS is disease progression/relapse or death.  PFS time is defined as the 
time from randomization to disease progression/relapse, death, or loss to follow-up 
whichever occurs first. Progression will be assessed using the standard RECIST 1.1 criteria.  
Patient who are alive and disease-free at the end of study will be censored at that time point.  
PFS probabilities will be estimated by arm using the Kaplan-Meier estimator. In an 
exploratory manner, a Cox proportional hazards model will be used to determine the effect 
of naloxegol on PFS. Adjustment for known prognostic factors (age, sex, stage [IIIB vs IV], 
smoking status [non-smoker or light smoker vs heavy smoker]) will be included in the model 
if feasible. The model will be stratified by ECOG PS and planned use of bevacizumab. 
7) The event for OS is death from any cause.  OS time is defined as the time from 
randomization to death or loss to follow-up whichever occurs first.  Patient who are alive at 
the end of the study will be censored at that time point.  OS will be analyzed in the same 
manner as PFS. 
8) MOR expression and activation will be included as a covariate in the linear mixed model 
from the analysis described in 13.4.2 1.  An interaction between MOR expression/activation 
and treatment will be evaluated.  
13.5  Study Monitoring 
13.5.1 Adverse Event Stopping Rule 
The stopping rule specified below is based on the knowledge available at study 
development.  We note that the Adverse Event Stopping Rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the conduct of the trial 
and in consideration of newly acquired information regarding the adverse event profile of 


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the treatment(s) under investigation.  The study team may choose to suspend accrual because 
of unexpected adverse event profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as  “possible”, “probable”, or “definite”) that satisfy the following: 
• 
If 5 or more patients in the first 20 treated patients (or 25% of all patients after 20 are 
accrued) experience a grade 4 or higher non-hematologic adverse event and there is a 
higher rate in the highest dose active treatment arm as opposed to the placebo arm. 
• 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
13.5.2 Accrual Monitoring Stopping Rule 
Slow Accrual: Patient accrual will be closely monitored by the study team on a monthly 
basis. If the accrual rate falls below 50% of the expected accrual rate, investigators will 
carefully review feedback from sites and consider taking measures to encourage patient 
enrollment. 
13.6  Study Reporting 
13.6.1  This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, and 
administrative information will be provided to the DSMB every 6 months as per NCI 
guidelines. 
13.6.2  Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrials.gov” web site. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov. 
 
 




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14.0 CORRELATIVE AND COMPANION STUDIES  
There will be 1 substudy and all patients are encouraged to participate.  
14.1 
Biological mechanism of action, and biomarkers that would predict response/risk to the 
study drug 
14.1.1 Background 
Biological end-points based on our hypothesis will be evaluated in tumor biopsies and 
plasma, pre-treatment and plasma post-treatment. For practical reasons, obtaining post-
treatment biopsies may not be feasible in this multi-center study. The hypothesis to be 
addressed is that high mu opioid receptors (MOR) in the tumors co-activates receptor 
tyrosine kinases for vascular endothelial growth factor receptor (VEGFR)-2 (on 
endothelium) and epidermal growth factor receptor (EGFR) on the tumor cells and 
downstream signaling pathways of mitogen activated protein kinase (MAPK/ERK) and 
protein kinase B (PKB/Akt) that promote cell proliferation and survival, respectively, and 
cyclo-oxygenase (COX)-2 signaling, leading to tumor progression and impairment of 
HRQoL. We anticipate that tumors with higher mu opioid receptor expression will show 
more responsiveness to naloxegol treatment and/or tumors with lower mu opioid receptor 
expression may show slower growth on their own. Thus, tumors with higher mu opioid 
receptors will show a correlative increase in the phosphorylation of endothelial VEGFR2, 
EGFR on endothelial/tumor cells, MAPK/ERK and Akt, Stat3 and increased COX-
2/prostaglandin (PG)-E2 in association with higher cell proliferation (by proliferating cell 
nuclear antigen: PCNA) and cell survival (TUNEL staining) indices. Pain can influence pro-
inflammatory and vasoactive neuropeptide substance P (SP), which can promote tumor 
growth-specific effects such as vascular permeability and angiogenesis, which may be 
higher in patients with more pain in association with beta-endorphin, the endogenous ligand 
for MOR. The levels of beta-endorphin and substance SP in the plasma will therefore 
correlate with increased MOR in the tumor and with pain. In addition, since opioid receptors 
can also modulate angiogenesis and lymphangiogenesis, these would correlate with MOR 
and opioid use and beta-endorphin levels. 
14.1.2 Objectives 
The main objective of the correlative science studies is to examine if MOR expression or 
activation is a prognostic marker in advanced NSCLC, and whether its expression/activation 
can be used to guide pain management. To examine this, the correlative studies will examine 
if any potential beneficial effect of selective peripheral MOR inhibition by naloxegol on 
HRQoL is limited to, or greater in, patients:  
• 
Whose tumors demonstrate a higher level of MOR expression/activation 
• 
With higher circulating levels of endogenous opioids, or 
• 
Those requiring higher doses (≥5 mg/day average oral morphine equivalents 
[OME]) of pharmacological opioids 
We will assess the mechanism of the study drug’s impact by analyzing whether the HRQoL 
differences between the arms are greatest: 1) in patients with higher than the median MOR 
expression on their tumors; 2) in those with higher than the median circulating endogenous 
opioids; and 3) in those taking ≥ 5 mg/day average oral morphine at the start of the trial. 
If our hypothesis proves to be true, this line of investigation can be further advanced in 
future studies to use fresh biopsies for isolating tumor cells and endothelial cells for 
mechanism based studies and can also be used in organ culture to determine the therapeutic 
potential of naloxegol on a case by case basis. 


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14.1.3 Methods 
Expression of opioid receptors and correlative growth and survival-promoting signaling 
pathways in the tumor biopsies:  
We provide the staining strategy with an example of one set of staining. Four to six micron 
thick sections will be co-stained with the following primary antibodies: goat anti-human 
CD31 (Santa Cruz Biotechnology, Santa Cruz, CA) at 1:50 dilution to label blood vessels, 
mouse anti-human total or phospho EGFR (Abcam, Cambridge, MA) at 1:100, and rabbit 
anti-human MOR (Chemicon International, Temecula, CA) at 1:100, followed by staining 
with species-specific secondary antibodies labeled with Cy2 (CD31), Cy3 (EGFR), and Cy5 
(MOR) (Jackson Immunoresearch, Westgrove, PA). z-stacks of 0.5 micron thick images 
will be acquired using LSCM (Olympus FluoView 1000 BX2, Olympus Corporation, Center 
Valley, PA) for all 3 markers in the same field of view (FOV). MOR will be pseudo-colored 
green, EGFR red, and CD31 blue using Adobe Photoshop, and images from the same FOV 
will be merged to analyze for co-expression of molecular markers as described by us 
previously.2 
Quantitative analysis of immunoreactive (ir) pixels for each marker: Each acquired image 
will be binarized and analyzed for immunoreactive pixels using Adobe Photoshop as 
described by us previously5 and expressed as ir pixels divided by total stained area. To 
reduce non-specific background all acquisitions will be thresholded similarly for a specific 
antibody. Data will be expressed as ir-pixels per FOV at a fixed magnification. 
Sets of markers examined will be as follows:  
CD31, MOR, phospho-VEGFR2, Total VEGFR2 
CD31, MOR, phospho-EGFR, Total EGFR 
CD31, MOR, phospho-MAPK/ERK, Total MAPK/ERK 
CD31, MOR, phospho-Stat3, Total Stat3 (this set will be tested if adequate number of 
slides are available) 
Quantitative analysis of SP and beta-endorphin in the plasma:  
SP will be analyzed in heparinized plasma using competitive ELISA (R&D Systems, 
Minneapolis, MN), using negative and positive controls with each set of analysis, as 
described by us.80 Levels of beta-endorphin will be determined in EDTA-plasma, using 
competitive high sensitivity ELISA (Peninsula Laboratories International, Inc, San Carlos, 
CA). We have standardized this assay and recognize that it has to be run at least in duplicate 
on each sample for reproducibility.  
These methods have been standardized in the investigator’s laboratory using human and 
mouse plasma. Quality control assessments have been performed on human plasma, which 
will also be used while analyzing the plasma samples from this current study. Longitudinal 
studies on beta-endorphin and SP have been performed on the plasma of transgenic mice 
during cancer progression. These longitudinal studies have shown a significant correlation 
between tumor burden and the concentration of beta-endorphin in the plasma. 
Anticipated Problems and Alternative Strategies 
Limited number of slides or no biopsy slides (FNA): In general, throughout the study we will 
stain for 3 markers/section. We will ask for 4-6 unstained slides per patient. Each slide will 
be stained for 4 markers if fewer slides are available using our established 
immunofluorescent labeling techniques.2,33,81 To maximize the analytical output and 
minimize the effect of regional heterogeneity, 3-5 different fields of view (FOV) will be 
imaged per section for each marker. All 4 markers per section will be analyzed in each FOV 


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and 2 sections will be stained per set of 4 markers. Therefore, with 4-6 slides we will be able 
to analyze 8-12 markers. However, based on our past experience with similar studies,2-5 we 
realize the challenges involved in obtaining slides from limited tissue biopsies and/or FNA. 
In our previous study, biopsies from about 30 tumors analyzed for MOR immunoreactivity 
yielded significance in an analysis similar to that proposed in the current study.5 In similar 
studies reported by other investigators, biopsies could not be available for analysis from all 
the patients, but significance could be achieved for the clinical correlations examined for 
intratumoral markers of hypoxia and angiogenesis with respect to % freedom from 
biochemical failure against time in years.82 We anticipate analyzing 10-12 markers, but in 
the event of limited availability we will limit our analysis to 6-8 most important markers, 
namely MOR; phospho and total-EGFR, phospho and total-VEGFR2, and anti-CD31; and 
total and phospho- MAPK/ERK and -Stat3, which can be performed on 2 unstained slides. 
In cases where FNA is performed, we will request slides from the paraffin cell block, if 
available. Therefore, we are cautiously optimistic of obtaining the targeted sample size for 
correlative analytical studies. 
Hemolysis: Another observation that we have made is occasionally blood samples are 
hemolyzed. The analysis using ELISA may be compromised on hemolyzed samples and 
they will need to be excluded from the study. To overcome this issue, we will examine the 
samples immediately upon arrival in the lab. If we find a hemolyzed sample, we will 
immediately contact the collecting center to consider the possibility of re-draw and replacing 
the sample. 
Exploratory outcomes:  
Measuring the circulating levels of beta-endorphin and SP is exploratory, but their 
translational potential is high for identifying novel markers of pain associated with tumor 
progression independently and also after opioid use. This is therefore a high risk, high 
reward analysis. It is based on our strong pre-clinical studies in cancer-bearing mice and in 
transgenic mice with sickle cell disease expressing human sickle hemoglobin, both of which 
experience constitutive chronic pain.33, 81,83 Studies by other groups on sickle patients have 
clearly shown an increase in blood levels of SP in sickle patients at steady state as compared 
to ethnicity- and age-matched controls; as well as a further increase in sickle patient’s blood 
during vaso-occlusive crises (VOC), a condition associated with acute severe pain.84 In our 
mouse studies, sickle mice showed significantly increased blood levels of SP at steady state 
compared to control mice expressing normal human hemoglobin A. Upon treatment with 
imatinib, cromolyn sodium, cannabinoids and an investigational drug (AT200), SP levels 
decreased significantly, and correlated with decreased pain following these treatments.80,85 
Complementary to these observations, transgenic breast cancer bearing mice showed 
increased SP expression in the tumors of mice receiving chronic morphine treatment as 
compared to those receiving PBS.33 These data provide convincing evidence of increased 
SP in the tumors and in the blood in response to pain as well as after treatment with 
morphine. Importantly, treatments influencing the pathobiology of the disease leading to 
decreased pain also led to a decrease in circulating SP. Together, these data in two conditions 
with chronic pain show that SP is modulated in response to disease pathobiology, pain and 
pain treatment. SP may therefore serve as a potential marker of pain and its response to 
therapy. In addition, since SP appears to mediate neurogenic inflammation and cancer 
progression in pre-clinical studies, its receptor NK1 provides an additional target to block 
the adverse effect of SP. Some NK1 receptor antagonists are FDA approved and can be 
utilized to reduce pain and/or reduce disease progression. Therefore, levels of SP will be 
critical to analyze and are likely to generate a novel hypothesis to be examined in future 
studies.  


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Timing of SP and beta-endorphin measurement:  
We realize that due to the complex and heterogeneous tumor microenvironment which is 
further influenced by stress and different treatments for cancer and/or pain, the circulating 
levels of ligands can vary considerably. In transgenic sickle mice with severe systemic 
inflammation and pain, and in transgenic cancer-bearing (C3TAg) mice which have an 
inflammatory milieu and pain, we found that inflammatory cytokines and SP were both 
significantly modulated as early as 5 days and as late as 7 weeks of treatment, the last period 
of observation.33,80,85,86 Therefore, we chose three time points for the current clinical study 
(i.e., at the start of the study to provide a baseline to compare subsequent effect of 
progression/treatments, and two relatively early time points [at 3 and 6 weeks]) with the 
expectation that we will detect a significant effect. Relatively early analysis of these 
biomarkers is important because it will provide a window of opportunity to offer additional 
treatment choices based on these biomarkers, such as NK1 antagonists if SP is increased or 
PAMORAs if beta-endorphin is increased. As described above, this would be supportive of 
our novel hypothesis of the role of pain associated mechanisms involving MOR/SP leading 
to the identification of actionable targets. We are cautiously optimistic of observing 
significant changes in the plasma levels of these markers within 6-8 weeks as compared to 
baseline and/or in response to therapy.  
Correlation of tumor progression, inflammatory response and pain:  
It is well known that inflammation is associated with both advanced cancer and pain 
independently as well as with cancer associated pain. In our pre-clinical studies, we 
observed a parallel increase in inflammatory cytokines and SP in the tumors of C3TAg mice 
treated with morphine.33 Similarly, in transgenic sickle mice we found a significant increase 
in inflammatory cytokines and SP in the plasma and their release from skin biopsies as 
compared to that of control mice.85 While SP levels were uniformly increased, individual 
cytokines released from the skin were variable and were further modulated in a 
heterogeneous manner with modulation of pain by different targeted therapies. Therefore, 
SP provides a more uniform measure of neuro-inflammation, which is relatively more 
specific to pain associated conditions. However, it could be an indicator of systemic 
inflammation as well. Therefore, its correlation with MOR may be critical for its association 
with pain leading to impairment of HRQoL.  
Correlation between SP and MOR expression:  
In pre-clinical studies, we found that treatment with morphine increased the expression of 
several inflammatory cytokines and SP in the tumors, correlating with increased tumor 
burden in transgenic C3TAg mice.33 Importantly, while MOR expression was undetectable 
in early/small tumors, there was high expression of MOR in large tumors. Consistent with 
this observation, morphine administration stimulated the growth of relatively large, but not 
small tumors (at the time of tumor initiation). 
Thus, increased MOR expression complements increased SP expression. This could occur 
in response to morphine treatment as observed by us in sickle mice, but also in response to 
increased beta-endorphin, a ligand for MOR. In our clinical study on patients with prostate 
cancer, we found that MOR expression in the tumor biopsies was independently associated 
with shorter time to progression, progression-free survival and overall survival, irrespective 
of opioid requirement for pain.5 Therefore, in the absence of exogenously administered 
opioids, activation of MOR (whose expression is increased in advanced tumors) is likely 
due to endogenous ligands such as endorphins, which may be increased due to stress and/or 
in response to pain. Our rationale to analyze beta-endorphin is further complemented by a 
recent study on cancer patients showing significantly increased plasma beta-endorphin 
levels in patients treated with the COX inhibitor drug flurbiprofen axetil in combination 


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with morphine as compared to morphine treatment alone, for 7 days.87 Satisfactory analgesia 
in this study was associated with increased plasma beta-endorphin levels as demonstrated 
by negative correlation between beta-endorphin in the plasma and pain scores (R2, 0.929 
and P<0.01). Therefore, beta-endorphin can be a prognostic marker for analgesia, in addition 
to its activation of mitogenic signaling via MOR in the tumors, plausibly contributing to 
cancer progression. Seminal observations from our group showed that like morphine, beta-
endorphin activated MAPK/ERK signaling in endothelial cells.1 Since both beta-endorphin 
and SP are released in conditions associated with pain and in response to morphine/pain 
treatment, their circulating levels may have a diagnostic as well as prognostic potential, with 
a bearing on improving HRQoL and clinical outcomes.  
Tumor specimens will be evaluated for expression of the following markers by analysis of 
images acquired using laser scanning confocal microscopy (LSCM):  
Mu opioid receptor2-5 
Kappa opioid receptor88 
COX-2 (partly mediates the pro-angiogenic activity of MOR)31  
Total and phosphorylated VEGFR2 and EGFR (cross-activated by MOR)2 
Total and phosphorylated Stat3, Akt and MAPK (phosphorylated by MOR 
activation)1,2,38,42  
Substance P (SP: marker of neurogenic inflammation and pain)85  
CD31 (marker of blood vessels, for assessment of microvessel density)2 
LYVE1 (marker of lymphatic vessels)33 
Circulating levels of beta-endorphin and SP will be determined in plasma samples 
obtained at registration and at 3 weeks (+/- 7 days) and 6 weeks (+/- 7 days) after 
initiation of the study medication. 
All analysis will be performed in a double blind manner. The assays and analyses proposed 
herein are routinely performed in Dr. Kalpna Gupta’s laboratory using antibodies for each 
marker that have been validated and published. Paraffin embedded tumor sections will be 
stained with three different primary antibodies and species-specific secondary antibodies 
tagged with different fluorophors. A montage of Z-stack images acquired using a LSCM 
will be analyzed to quantitate immunoreactive (ir) pixels for each marker using Adobe 
Photoshop and Image Processing tool-kit Plug-in functions (Reindeer Games, Ashville, NC) 
as described by us.5  
The tumor microenvironment is composed of several different cellular entities critical to 
cancer progression which express opioid receptors, including tumor-, endothelial and 
lymphatic cells, of direct relevance to this proposal. Therefore, opioid-receptor associated 
activity will be analyzed in a cell-specific manner. Since associations with MOR will be 
defined, co-staining will be performed for each marker with MOR using three color 
immunostaining of tumor sections. 
Expected results:  
High MOR expression will be associated with endothelial, lymphatic and tumor cells. 
VEGFR2 phosphorylation associated with MOR will only be observed in the vasculature, 
whereas EGFR, Stat3 and MAPK/ERK will be observed in endothelial as well as non-
endothelial cells. It is likely that higher MOR-ir will be accompanied by decreased kappa 
opioid receptor-ir, suggestive of increased MOR activity as compared to kappa opioid 
receptor in the tumors when opioids are used to treat pain. Correlative analysis with survival 
will reveal the significance of the mechanisms involved and additional targets to develop 


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strategies to ameliorate MOR-associated disease progression. Due to increased stress and 
pain, circulating levels of beta-endorphin and SP will be higher in subjects with higher 
disease burden, progression and pain. These will be even higher in subjects on higher doses 
of opioids, but may be attenuated in those receiving naloxegol that blocks peripheral opioid 
receptors. In this pilot study, statistical analysis of these correlative studies will be 
exploratory and hypothesis-generating. 
Potential for future clinical translation:  
Importantly, these correlative studies performed in a clinical setting will identify the 
receptors and signaling pathways activated in association with MOR. This would lead to 
future investigations to determine mechanisms underlying MOR-induced co-activation of 
these specific signaling pathways in human endothelial and/or cancer cells. In turn, these 
observations will provide targets to block MOR-induced tumor progression without 
compromising analgesia. Additionally, if we observe an inhibitory effect of naloxegol on 
mitogenic signaling pathways in the tumor, it could be further examined for its effect in 
combination with standard systemic anti-cancer therapies to improve clinical outcomes 
including HRQoL.   
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
None 
 


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94. Zhang YF, Xu QX, Liao LD, Xu XE, Wu JY, Wu ZY, Shen JH, Li EM and Xu LY. Association of 
mu-opioid receptor expression with lymph node metastasis in esophageal squamous cell carcinoma. 
Dis Esophagus. 2015;28:196-203. 
95. Yao YS, Yao RY, Zhuang LK, Qi WW, Lv J, Zhou F, Qiu WS and Yue L. MOR1 expression in 
gastric cancer: a biomarker associated with poor outcome. Clin Transl Sci. 2015;8:137-142. 
 
 
 
 
 


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17.0 MODEL CONSENT FORM 
 
Study Title for Study Participants: Testing the addition of naloxegol 
(Movantik®) or placebo to anti-cancer therapy in advanced lung cancer 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  
A Randomized, Double-Blind, Placebo-Controlled Pilot Study Of An Oral, 
Selective Peripheral Opioid Receptor Antagonist In Advanced Non-Small Cell 
Lung Cancer  
 
What is the usual approach to my lung cancer? 
You are being asked to take part in this study because you have been diagnosed with a common 
type of advanced lung cancer (non-small cell lung cancer: NSCLC). You have also used pain 
medicines (such as morphine or similar drugs, called opioids) in the past 4 weeks to control pain 
caused by your cancer. People who are not in a study are usually treated with a variety of FDA-
approved medications. Many patients with advanced lung cancer also require opioid pain 
medications to control pain at some time during the course of their disease. 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above 
• you may choose to take part in a different study, if one is available 
• or you may choose not to be treated for cancer but you may want to receive comfort 
care to relieve symptoms. 
 
Why is this study being done? 
You have advanced lung cancer and will be receiving opioids to relieve some of the cancer-
related pain that you are experiencing. Opioids relieve pain through their action inside the brain. 
However, by their action outside of the brain, opioid medications can cause unwanted side 
effects such as constipation, nausea, vomiting, dry mouth, and problems passing urine.  
 
The purpose of this study is to test the safety and effects of naloxegol. Naloxegol is a medicine 
that blocks the actions of opioids outside the brain, without interfering with the pain-relieving 
effect of opioids inside the brain. The researchers want to see if naloxegol will relieve some of the 
side effects of the opioid pain medications you are taking. They also want to see if naloxegol fights 
off future growth in the cancer that you have, whether or not you are taking pain medications. 
 
The effect of two different doses of naloxegol will be compared to placebo. A placebo is a pill 
that looks like the study drug but contains no medication.  




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time. Please swallow tablets whole, do not crush or chew. The tablets in the two bottles will look 
different from each other. One or both of the tablets could be a placebo.  
 
You should not have grapefruit or grapefruit juice while on this study. You should also check 
with your doctor or pharmacist before using any new medicines, including over-the-counter 
drugs because of possible drug interactions.  
 
You will be asked to record the day, number of pills taken, and time of each dose of 
naloxegol/placebo on a medication diary. You will be asked to bring the calendar and the pill 
bottles with you to your clinic visits.  You will also be asked to record how much pain you are 
feeling and any pain medications you may have taken on another form.   
 
How long will I be in this study? 
 
You will receive naloxegol/placebo for up to 2 years or until you experience any severe side 
effects. If you receive naloxegol/placebo for 2 years, you may choose to find out at that time 
whether you were receiving naloxegol or placebo.  If you were receiving naloxegol, you and 
your doctor will decide whether you should continue taking naloxegol.  The study will not 
provide naloxegol after 2 years. 
 
Whether or not you remain on study treatment, the study doctor will continue to follow your 
progress. 
 
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests (such as blood tests), and procedures (such as CT or other scans) you 
will have are part of the usual treatment and monitoring of your cancer. However, there are some 
extra tests that you will need to have if you take part in this study. 
 
 
Before you begin the study medication: 
You will complete some questionnaires before you start taking your study drug. 
 
 
During the study: 
You will be asked to come to the clinic for follow-up about 3 and 6 weeks after starting the study 
medication to see how you are doing physically and check your blood tests.  
 
You will also be asked to complete questionnaires 3 weeks and 6 weeks after you start 
naloxegol/placebo, and then every 3 weeks for one year and then every 3 months. These surveys 
will be about your pain medications, your urinary functions, your bowel movements and your 
quality of life. This should take about 15 minutes to complete.  
 


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A patient study calendar that shows how often these tests, and questionnaires will be done is 
attached at the end of this document. 
 
If you do not come to the clinic at these times, you may either mail the questionnaires to your 
study doctor, or the clinic staff may obtain the information needed from you over the phone. 
 
 
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
• The addition of naloxegol to usual anti-cancer therapy may not be better, and could 
possibly be worse, than the usual anti-cancer therapy given by itself for your cancer. 
The Naloxegol used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from naloxegol. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust naloxegol/placebo to try to reduce side effects. 
 
 
 


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The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
Possible Side Effects of Naloxegol 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Naloxegol, more than 20 and up to 100 may have: 
• 
Pain in the abdomen (stomach) 
 
 
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving Naloxegol, from 4 to 20 may have: 
• Diarrhea 
• Nausea 
• Flatulence (bloating, gas) 
• Vomiting 
• Headache 
 
RARE, SOME MAY BE SERIOUS  
In 100 people receiving Naloxegol, 3 or fewer may have: 
• 
Perforation (tear) in the wall of the stomach, intestines or bowel  
• 
Symptoms due to blocking the effect of opioids (“opioid withdrawal”), such as 
excessive sweating, chills, diarrhea, pain in the abdomen (stomach), anxiety, 
irritability, and yawning. 
 
Let your study doctor know of any questions you have about possible side effects. You can ask 
the study doctor questions about side effects at any time. 
 
The topics discussed in questionnaires may cause you to feel embarrassed or uncomfortable. If 
this happens to you, please let your study doctor, nurse or other study staff know about your 
discomfort. 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. 
The study medication naloxegol/placebo used in this study could be very damaging to an unborn 
baby. Check with the study doctor about what types of birth control, or pregnancy prevention, to 
use while in this study. 
 
What possible benefits can I expect from taking part in this study? 
It is not possible to know at this time if addition of naloxegol/placebo to standard anti-cancer 
therapy is better than the usual approach (anti-cancer therapy) so this study may or may not help 
you. This study will help researchers learn things that will help people in the future. 
 


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Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB or FDA. 
 
What are my rights in this study? 
 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number).  
 
What are the costs of taking part in this study? 
 
Naloxegol/placebo will be supplied at no charge for up to 2 years while you take part in this 
study. The cost of getting the naloxegol/placebo ready and giving it to you is also provided at no 
charge. It is possible that the naloxegol/placebo may not continue to be supplied while you are 
on the study. Although not likely, if this occurs, your study doctor will talk to you about your 
options. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of 
treating your cancer while in this study, including the cost of tests, procedures, or medicines to 
manage any side effects, unless you are told that certain tests are supplied at no charge. Before 
you decide to be in the study, you should check with your health plan or insurance company to 
find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 


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What happens if I am injured or hurt because I took part in this study? 
 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for 
injury. Your insurance company may not be willing to pay for study-related injury. If you have 
no insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
Who will see my medical information? 
 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
• The study sponsor and any drug company supporting the study.  
• The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and 
similar ones if other countries are involved in the study. 
 
The Alliance has received a Certificate of Confidentiality from the federal government, which 
will help us to protect your privacy. The Certificate protects against the involuntary release of 
information about you collected during the course of the study. The researchers involved in this 
project may not be forced to identify you in any legal proceedings (criminal, civil, 
administrative, or legislative) at the federal, state or local level. However, some information may 
be required by the Federal Food, Drug, and Cosmetic Act, the U.S. Department of Health and 
Human Services, or for purposes of program review or audit. Also, you may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if you 
or your guardian requests the release of information about you in writing (through, for example, 
a written request to release medical records to an insurance company), the Certificate does not 
protect against that voluntary disclosure. 
 


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Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
Who can answer my questions about this study? 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
ADDITIONAL STUDIES SECTION:  
This section is about optional studies you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in. You 
will not get health benefits from any of these studies. The researchers leading this optional study 
hope the results will help other people with cancer in the future. 
 
The results will not be added to your medical records and you or your study doctor will not know 
the results. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say “no” to any or all of these studies. If you sign up for but cannot complete any of the 
studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
 
 


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Optional Sample Collections for Laboratory Studies and/or Biobanking for 
Possible Future Studies 
Researchers are trying to learn more about pain, cancer, and other health problems. Much of this 
research is done using samples from your blood or tissue. Through these studies, researchers 
hope to find new ways to prevent, detect, treat, or cure health problems. 
 
Some of these studies may be about genes. Genes carry information about features that are found 
in you and in people who are related to you. Researchers are interested in the way that genes 
affect how your body responds to treatment. 
 
If you choose to take part in this study, the study doctor for the main study would like to collect 
blood for research on substances in the body that cause pain and others that relieve pain. Researchers 
would also like to study samples from your lung cancer tissue that were obtained from you for 
diagnosis. The tissue will be analyzed for factors that are involved in causing pain and others that 
are involved in promoting tumor growth. We are asking for your permission to store and use 
your samples and related health information (for example, your response to cancer treatment, 
results of study tests and medicines you are given) for medical research. The research that may 
be done is unknown at this time. Storing samples for future studies is called “biobanking”. The 
Biobank is being run by the Alliance Biorepository at Mayo Clinic and supported by the 
National Cancer Institute. 
 
WHAT IS INVOLVED? 
If you agree to take part, here is what will happen next: 
1) About two extra teaspoons of blood will be collected from a vein in your arm once 
before starting the study medication and twice more (at about 3 and 6 weeks) after 
you start the study medication). All these blood samples will be collected at the time 
you are giving blood samples for routine (usual) tests related to your anti-cancer 
therapy. You will NOT have to undergo extra needle sticks to provide blood samples 
for these laboratory studies. 
2) In addition, a sample from the tissue that was collected previously at the time of your 
biopsy or surgery will be sent to the Biobank. You will NOT be asked to undergo 
another biopsy to provide tissue for these laboratory studies. 
3) Your sample and some related health information will be sent to a researcher for use 
in the study described above. Remaining samples may be stored in the Biobank, along 
with samples from other people who take part. The samples will be kept until they are 
used up. 
4) Qualified researchers can submit a request to use the materials stored in the Biobanks. 
A science committee at the clinical trials organization, and/or the National Cancer 
Institute, will review each request. There will also be an ethics review to ensure that 
the request is necessary and proper. Researchers will not be given your name or any 
other information that could directly identify you.  
5) Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your samples.  
6) Some of your genetic and health information may be placed in central databases that 
may be public, along with information from many other people. Information that 
could directly identify you will not be included. 


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WHAT ARE THE POSSIBLE RISKS? 
1) The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise.  
2) There is a risk that someone could get access to the personal information in your 
medical records or other information researchers have stored about you. 
3) There is a risk that someone could trace the information in a central database back to 
you. Even without your name or other identifiers, your genetic information is unique 
to you. The researchers believe the chance that someone will identify you is very 
small, but the risk may change in the future as people come up with new ways of 
tracing information. 
 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your samples are sent to the researchers, no information identifying you (such 
as your name) will be sent. Samples will be identified by a unique code only.  
2) The list that links the unique code to your name will be kept separate from your 
sample and health information. Any Biobank and Alliance for Clinical Trials in 
Oncology staff with access to the list must sign an agreement to keep your identity 
confidential. 
3) Researchers to whom Alliance for Clinical Trials in Oncology send your sample and 
information will not know who you are. They must also sign an agreement that they 
will not try to find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not 
be used. 
 
WHAT ARE THE POSSIBLE BENEFITS? 
You will not benefit from taking part in these laboratory studies. The results may help other 
patients in the future.  
 
ARE THERE ANY COSTS OR PAYMENTS? 
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
WHAT IF I CHANGE MY MIND? 
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at ________________________ 
(insert telephone number of study doctor for main trial) who will let the researchers know. Then, any 
sample that remains in the bank will no longer be used and related health information will no 
longer be collected. Samples or related information that have already been given to or used by 
researchers will not be returned. 
 


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WHAT IF I HAVE MORE QUESTIONS? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ (insert 
telephone number of study doctor for main trial). 
 
Please circle your answer to show whether or not you would like to take part in each option: 
 
SAMPLES FOR THE LABORATORY STUDIES: 
I agree to have my specimen collected and I agree that my specimen sample(s) and 
related information may be used for the laboratory study(ies) described above. 
 
 
YES 
 
NO 
 
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
My samples and related information may be kept in a Biobank for use in future health 
research. 
 
 
YES 
 
NO 
 
I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent 
discussion___________________________________ 
 
Date of signature_____________________________________ 
 
 
 


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The following table summarizes your visit schedule for this study: 
 
 
Prior to 
the study 
3 and 6 weeks 
after start of 
treatment 
Every 6 weeks* 
until 1 year after 
start of treatment  
Every 3 
months 
Tests & 
Assessments 
 
 
 
 
History and physical 
X 
 
 
 
Blood Tests 
X 
X 
 
 
Monitoring 
X 
X 
X** 
X 
Questionnaire 
booklets 
X 
X 
X*** 
X 
Patient Medication 
Diary  
 
X 
X 
X 
 
* 
You may be asked to visit the clinic more often than every 6 weeks.   
** 
Monitoring will take place every 3 weeks. If you do not see your study doctor every 3 
weeks, this monitoring will be done by telephone. 
*** 
Some questionnaire booklets will be required every 3 weeks. 
 
 


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APPENDIX I: PAIN AND PAIN MEDICATION DIARY 
[This version is to be used in the baseline Booklet A.] 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one row for each 7-day-period of treatment. 
2. 
Record the name, strength, and number of doses of pain medication you took per day during the past 7 
days and how much pain you had on average during the 7-day period.  
Did you take any pain 
medication(s) during 
this 7-day period? 
If yes, name(s) of the 
medication(s) 
Strength(s) 
Average number 
of doses per day 
taken during this 
7-day period 
Average level of pain during 
this 7-day period (0-10, with 
10 being worst pain 
imaginable) 
 
 
 
 
 
 
 
 
 


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[This version is to be used in the every-three-week Booklet C.] 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one row for each 7-day-period of treatment. 
2. 
Record the date, the name, strength, and number of doses of pain medication you took per day during 
each 7-day period, and how much pain you had on average during each 7-day period.  
3. 
Use the last rows only if you need them. 
Week 
Date 
(first day 
of each 7-
day 
period 
Did you take 
any pain 
medication(s) 
during this 7-
day period? 
If yes, name(s) of the 
medication(s) 
Strength(s) 
Average number 
of doses per day 
taken during this 
7-day period 
Average level of 
pain during this 7-
day period (0-10, 
with 10 being worst 
pain imaginable) 
1. 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician’s Office will complete this section: 
 
1. Date patient started protocol treatment 
___________________________________________________ 
 
2. Date patient was removed from study ____________________________________________________ 
 
3. Physician/Nurse/Data Manager’s Signature  
 
_________________________________________________ 
 
 
 
 


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[This version is to be used in the every-three-month Booklet D.] 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one row for each 7-day-period of treatment. 
2. 
Record the date, the name, strength, and number of doses of pain medication you took per day during 
each 7-day period, and how much pain you had on average during each 7-day period.  
3. 
Use the last rows only if you need them. 
Week 
Date 
(first day 
of each 7-
day 
period 
Did you take 
any pain 
medication(s) 
during this 7-
day period? 
If yes, name(s) of the 
medication(s) 
Strength(s) 
Average number 
of doses per day 
taken during this 
7-day period 
Average level of 
pain during this 7-
day period (0-10, 
with 10 being worst 
pain imaginable) 
1. 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 


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9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician’s Office will complete this section: 
 
1. Date patient started protocol treatment 
___________________________________________________ 
 
2. Date patient was removed from study ____________________________________________________ 
 
3. Physician/Nurse/Data Manager’s Signature  
 
_________________________________________________ 
 
 
 
 
 
 


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APPENDIX II: PATIENT MEDICATION DIARY – NALOXEGOL/PLACEBO 
Today’s date ______________________________ 
 
Patient Name___________________ (initials acceptable)  
Patient Study ID ____________ 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete this form while you take naloxegol/placebo.  This form is a 30 day diary.  You may 
need to complete more than one form between clinic visits. 
2. 
You will take your dose of naloxegol/placebo daily.  
3 
Take the naloxegol/placebo pills at least one hour before a meal or at least two hours 
afterwards. 
4. 
Record the date, the number of tablets you took, and when you took them. Record doses as soon 
as you take them; do not batch entries together at a later time. 
5. 
If a dose is missed, do not make up that dose; resume dosing with the next scheduled dose. 
6. 
Swallow tablets whole, do not crush or chew. 
7. 
You should not have grapefruit or grapefruit juice while on this study. 
In rare cases this medication can cause the following side effects:  
a)  If you develop unusually severe, persistent or worsening pain in your abdomen. 
b)  If you are unable to pass stools and gas, and your abdomen feels uncomfortably bloated. 
If these occur, stop taking the naloxegol/placebo pills and call your doctor/health care provider. 
8. 
If you have any comments or notice any side effects, please record them in the Comments 
column. If you make a mistake while you write, please cross it out with one line, put your initials 
next to it, and then write the corrected information next to your initials.  Example: 10:30 am SB 
9:30 am 
9. 
Please return this form to your physician at your next appointment. You may need to return more 
than one form per clinic visit. You will also be asked to return your pill bottles at each visit. 
 
 


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Day 
Date 
Time of daily dose 
Bottle #1 
# of tablets taken 
Bottle #2 
# of tablets taken 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
29 
 
 
 
 
 
30 
 
 
 
 
 
Patient’s Signature 
 
 
Date 
 
 
 


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APPENDIX III: CALCULATION OF EQUI-ANALGESIC DOSES OF OPIOID MEDICATIONS  
Conversion of other opioid medications to Oral Morphine Equivalents (OME) 
 
To calculate the total oral morphine equivalents (OME) that a patient is using: 
1) Calculate the total dose of each opioid used per day. The doses of long-acting opioids or liquid 
preparations are calculated exactly as for short-acting or immediate release opioids. 
2) Multiply that total amount by the number for that opioid from the table below (e.g. 1.5 for oral 
oxycodone), to get the OME.  
3) Add up all the OMEs to get the total OME, as illustrated in the examples below. 
 
 
Opioid 
Parenteral (IV/IM/SC, in mg) 
Oral (mg) 
 
Multiplication factor 
Multiplication factor 
Buprenorphine 
75 
- 
Butorphanol 
15 
- 
Codeine 
0.25 
0.15 
Fentanyl 
300 
2*  
(transdermal: see below) 
Hydrocodone 
- 
1 
Hydromorphone 
20 
4 
Levorphanol 
15 
7.5 
Meperidine 
0.4 
0.1 
Methadone** 
13.5 
4.7 
Morphine 
3 
1 
Nalbuphine 
3 
- 
Oxycodone 
- 
1.5 
Oxymorphone 
30 
3 
Tapentadol 
- 
0.4 
 
*Multiply the fentanyl patch strength by 2 to get the OME directly. Thus, a 25 microgram/hour fentanyl 
patch = 50 OME.89  
 
 
Example 1: 
 
The patient is using MS Contin 30 mg PO BID + oxycodone/acetaminophen (Percocet; 5 mg/325 mg 
strength) 2 tabs every 6 hours (for breakthrough pain): 
 
MS Contin 30 mg x 2 times/day = 60 mg/day 
Multiply 60 by 1 (the number for oral morphine) = 60 x 1 = 
 
60 OME 
+ 
Oxycodone 5 mg x 2 tabs x 4 times/day = 40 mg/day 
Multiply 40 by 1.5 (the number for oral oxycodone) = 40 x 1.5 =  
60 OME 
 
Total OME = 60 + 60 =  
 
 
 
 
 
120 OME 
 
 
 


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Example 2: 
 
The patient is using a fentanyl patch 50 micrograms/hour strength + morphine elixir (10 mg/5 ml 
strength) 5 ml every 4 hours (for breakthrough pain): 
 
Fentanyl 50 micrograms/hour  
Multiply 50 by 2 (*see above) = 50 x 2 =  
 
 
 
 
100 OME 
+ 
Morphine elixir 10 mg x 6 times/day = 60 mg/day 
Multiply 60 by 1 (the number for oral morphine) = 60 x 1 = 
 
 
60 OME 
 
Total OME = 100 + 60 = 
 
 
 
 
 
 
160 OME 
 
 
 
 
**For conversion of methadone to OMEs, we will use the conversion factors recommended by Walker et 
al.90 This is a carefully conducted analysis of patients who switched from IV or oral methadone to morphine 
or other opioids. The authors recommend using a ratio of 1:4.7 for conversion of oral methadone to oral 
morphine, and a ratio of 1:13.5 for conversion of IV methadone to oral morphine. Of note, the conversion 
ratio remained constant (did not change) with increasing dose of methadone, unlike the change in ratio 
recommended when the conversion is in the opposite direction, i.e. when morphine is converted to 
methadone.91  
 
 
 


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APPENDIX IV: BOWEL FUNCTION-DIARY (BF-DIARY) 
 
Module 1: Characteristics of last bowel movement 
Please record the time when this bowel movement 
occurred. 
 
 
 
Hour/min. 
How much did you have to strain during this bowel 
movement? 
 Not at all 
 Slightly 
 Moderately 
 Quite a bit 
 Extremely 
During this bowel movement, how much did you feel 
that you were able to fully empty your bowels? 
 Not at all 
 Slightly 
 Moderately 
 Quite a bit 
 Completely 
How much pain did you have around your rectum 
during this bowel movement? 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
During this bowel movement, how would you 
describe the shape and consistency of your stool? 
 Separate hard lumps, like nuts (hard to pass) 
 Sausage-shaped but lumpy 
 Like sausage but with cracks on its surface 
 Like a sausage or snake, smooth and soft 
 Soft blobs with clear-cut edges (passed easily) 
 Fluffy pieces with ragged edges, a mushy stool 
 Watery, no solid pieces (entirely liquid) 
 
 
 


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Module 2: Past 24-hour Assessment 
In the past 24 hours, how often were you unable to 
have a bowel movement even though you felt like you 
had to? 
 All of the time 
 Most of the time 
 Some of the time 
 A little of the time 
 None of the time 
In the past 24 hours, how much bloating did you feel 
because of constipation? 
 None 
 Very mild 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the past 24 hours, how much pain did you feel in 
your abdomen because of constipation? 
 None 
 Very mild 
 Mild 
 Moderate 
 Severe 
 Very severe 
In the past 24 hours, how much were you bothered by 
gas? 
 Not at all 
 Slightly 
 Moderately 
 Quite a bit 
 Extremely 
In the past 24 hours, how much were you bothered by 
a lack of appetite because of constipation? 
 Not at all 
 Slightly 
 Moderately 
 Quite a bit 
 Extremely 
 
 
From: Camilleri M, Rothman M, Ho KF, Etropolski M. Validation of a bowel function diary for assessing opioid-
induced constipation. Am J Gastroenterol. 2011;106(3):497-506.78 
 
 






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None  
 
 
 
 
 
 
As bad as I can imagine 
 
 








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APPENDIX VII: PATIENT INFORMATION SHEETS  
 
 
 


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PATIENT INFORMATION SHEET 
Patient Completed Booklet A 
(Baseline) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer.  Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
1. You are being asked to complete a questionnaire booklet for this study. This booklet must be 
completed on the day you enroll in the study. It contains the following questionnaires: 
 
• 
FACT-L Questionnaire 
• 
PRO-CTCAE and Urinary Hesitancy Question 
• 
Bowel Function Diary 
• 
Pain and Pain Medication Diary 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3.  It is very important that you return the booklets to us, whether you finish the study or not. 
 
4. You will be given the nurse’s or study coordinator’s name and telephone number. You can call 
anytime with any concerns or questions. 
 
5. After completing this booklet, please return it to your nurse or physician. 
 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 


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PATIENT INFORMATION SHEET 
Patient Completed Booklet B 
(3 and 6 weeks after the start of treatment, then every 6 weeks for the first year of treatment) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer.  Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
1. You are being asked to complete this questionnaire booklet at the following time points: 
• 
3 weeks after the start of treatment 
• 
6 weeks after the start of treatment 
• 
Every 6 weeks for first year of treatment (i.e. week 12, week 18, week 24, etc.) 
 
2. This booklet contains the following questionnaires:  
• 
FACT-L Questionnaire 
 
3. Directions on how to complete each set of questions are written on the top of each set. 
 
4.  It is very important that you return the booklets to us, whether you finish the study or not. 
 
5. You will be given the nurse’s or study coordinator’s name and telephone number. You can call 
anytime with any concerns or questions. 
 
6. After completing this booklet, please return it to your nurse or physician or mail it back in the 
provided envelope. 
 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 


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PATIENT INFORMATION SHEET 
Patient Completed Booklet C 
(Every 3 weeks for the first year of treatment) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer.  Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
1. You are being asked to complete this questionnaire booklet every 3 weeks during the first year of 
your study treatment. It contains the following questionnaires: 
 
• 
PRO-CTCAE and Urinary Hesitancy Question  
• 
Bowel Function Diary 
• 
Pain and Pain Medication Diary 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3.  It is very important that you return the booklets to us, whether you finish the study or not. 
 
4. You will be given the nurse’s or study coordinator’s name and telephone number. You can call 
anytime with any concerns or questions. 
 
5. After completing this booklet, please return it to your nurse or physician or mail it back in the 
provided envelope. 
 
 
 
Thank you for taking the time to help us. 
 
 
 


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PATIENT INFORMATION SHEET 
Patient Completed Booklet D 
(Every 3 months after the first year of treatment) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer.  Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. After the first year of your study treatment, you are being asked to complete this questionnaire 
booklet every 3 months (month 15, month 18, month 21, etc.). It contains the following 
questionnaires: 
 
• 
FACT-L Questionnaire 
• 
PRO-CTCAE and Urinary Hesitancy Question 
• 
Bowel Function Diary 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3.  It is very important that you return the booklets to us, whether you finish the study or not. 
 
4. You will be given the nurse’s or study coordinator’s name and telephone number. You can call 
anytime with any concerns or questions. 
 
5. After completing this booklet, please return it to your nurse or physician. 
 
 
Thank you for taking the time to help us. 
 
 
 


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PATIENT INFORMATION SHEET 
Patient Completed Booklet E 
(Every 3 months after the first year of treatment) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  This booklet contains some questions about 
your ‘quality-of-life’ as a patient receiving treatment for cancer.  Your answers will help us to better 
understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. After the first year of your study treatment, you are being asked to take this booklet home and 
complete it every week.  You should return the booklet when you return to the clinic every 3 
months (month 15, month 18, month 21, etc.) after the first year of study treatment. It contains the 
following questionnaire: 
 
• 
Pain and Pain Medication Diary 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3.  It is very important that you return the booklets to us, whether you finish the study or not. 
 
4. You will be given the nurse’s or study coordinator’s name and telephone number. You can call 
anytime with any concerns or questions. 
 
5. After completing this booklet, please return it to your nurse or physician or mail it back in the 
provided envelope. 
 
 
 
Thank you for taking the time to help us. 
 
 
 


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APPENDIX VIII: HEMOLYZED PLASMA SAMPLES 
 
Please note that hemolyzed plasma samples are NOT acceptable. Please re-draw if the samples are 
hemolyzed. Below is a picture demonstrating different levels of hemolysis in plasma. Please be aware that 
even mild hemolysis is not acceptable for this study plasma submission.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IX: NALOXEGOL WALLET CARD 
 
[Note to investigators:  This convenient wallet-sized information card is to be completed and then 
provided for the patient to clip out and retain at all times.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial of naloxegol (Movantik®).   This 
clinical trial is sponsored by the National Cancer institute (NCI).  
Certain drugs may change the levels of liver enzymes such as 
CYP3A4 which process or break down naloxegol in the body. In 
addition, naloxegol may change levels of CYP3A4 and this may 
change how other medications are broken down. Because of this, it 
is very important to: 
 Tell your doctors if you stop taking regular medicine or if you 
start taking a new medicine. 
 Check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 
 
 Tell all of your prescribers (doctors, physician assistants, 
nurse practitioners or pharmacists) that you are taking part in 
a clinical trial. 
 Before you enroll onto this clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are strong inducers 
or moderate/strong inhibitors of CYP3A4  
 Before prescribing new medicines, your regular prescribers 
should go to 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is 
and can be contacted at