Clinical trial NCT03071744
Conditions: Bone Metastases
Sponsor: Joseph Ma
Start date: 2017-03-01; Completion date: 2018-03-09
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Advanced cancer patients often require palliative (pain relieving) radiotherapy to treat cancer-related symptoms. The delivery of radiation requires patients to lie still on a hard flat surface, which can result in significant acute (intense) pain and/or breakthrough cancer pain (sudden sharp or stabbing pain), especially when painful bone metastases are present. The current care for most cancer patients receiving radiation is to take an oral (by mouth) opioid medication before the radiation treatment. The pain relieving effects of these medications can take about one hour and can last for 3 to 6 hours, which does not follow the time course of when breakthrough cancer pain occurs.

Lazanda is a pain medication delivered via an intranasal route and is already approved by the U.S. Food and Drug Administration (FDA) for the management of breakthrough cancer pain for patients who are already receiving opioids and who can tolerate opioids for the treatment of cancer pain. Lazanda is fast-acting and convenient for patients to take. The purpose of this study is to assess the change in pain intensity during palliative radiotherapy following study treatment with Lazanda. This study will also explore the impact of the study treatment on the efficiency in delivering the radiation therapy

Detailed description:
This is a Phase II, single-center, single-arm, Open-Label Study to Evaluate Lazanda in Cancer Patients Receiving Palliative Radiation.

The primary objective of this study is to assess the change in patient reported positional pain intensity (PI) as measured by an 11-point numerical rating scale (NRS-11) in cancer patients with bone metastases assessed at a simulation visit and each subsequent daily palliative radiation fraction. The primary objective will be measured using the pain intensity difference (PID) of the NRS-11 from the time of laying down on the hard surface (0 minutes/ PI0) to the 15 minutes after laying down on the hard surface timepoint at baseline (the simulation visit) and at each subsequent study visit (PID15= PI0- PI15).

Study participants will be recruited across all oncology disease teams. Potential participants will be identified in weekly palliative care or disease team patient triage meetings. In order to meet eligibility for participation, a patient must be greater than or equal to 18 years old, have histologically-confirmed cancer with symptomatic bone metastases, an Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 3, and are planned to receive hypofractionated palliative radiation less than or equal to 10 fractions. Qualifying subjects must be opioid-tolerant, defined as greater than or equal to 60mg morphine or equivalent, and be on a stable dose of oral opioids for greater than or equal to 1 week. Stable baseline opioid dosage is defined as a dosage that does not fluctuate by more than 50% from the average dosage over one week prior to screening. Patients must also be on a stable dose of adjuvant pain therapies for one week prior to screening. Patients will be excluded if they are receiving or have received another investigational agent within 30 days or monoamine oxidase inhibitor within 14 days prior to Lazanda administration, have known hypersensitivity to fentanyl or opioids, have known, planned interventional procedures such as surgery that may affect study outcomes, are pregnant or nursing, have a disorder or current medication use likely to adversely affect normal functioning of the nasal mucosa, have uncontrolled or rapidly escalating background pain, or are medically unstable, require immobilization with a thermoplastic mask for radiation treatment.

Upon confirmation of all eligibility criteria, the subject will be enrolled. Each enrolled subject will undergo a baseline evaluation on a mock hard surface within 1 week prior to the time of CT simulation, to establish baseline NRS pain scores.

Subject will receive Lazanda at their mock hard surface visit , radiation simulation visit and again as pre-medication prior to each radiation treatment (fraction), for an estimated treatment period of 10 days based on the patient's radiation treatment plan. Lazanda will be self-administered intranasally by subjects participating in this study.

NRS pain scores will be collected at three time points at baseline : 15 minutes prior to laying on the hard surface (T-15), at the time of laying on the hard surface (T0), and at 15 minutes after laying on the hard surface(T+15). Exact time of each pain score rating will also be collected.

After the mock visit subject will then undergo radiation therapy simulation procedures (within approximately 2 weeks of radiation therapy) followed by hypofractionated radiation therapy, according to University of California, San Diego (UCSD) Radiation Oncology standard procedure and treatment plan determined by the subject's radiation oncologist. During radiation simulation and daily during each visit to the radiation center for hypofractionation delivery, subjects will have vital signs and weight collected. An ECOG performance status will also be assessed daily during radiation therapy. At the time of radiation simulation and daily during radiation therapy, subjects will complete the BPI-sf , Medication Use Diary, Laxation Diary, and Nausea/Vomiting Diary. As with the mock hard surface evaluation, NRS pain scores will also be collected at three time points during each visit to the radiation center.

Subjects will receive study drug, Lazanda at 100mcg dose, 15 minutes prior to simulation (T-15) at the radiation therapy simulation visit. Lazanda dose titration will follow the guidelines as indicated in the product package insert from the radiation simulation visit through the end of radiation therapy.

Subjects will undergo a post treatment follow-up period after completion of their radiation therapy. During this follow-up period, subjects will complete the BPI-sf, Medication Use Diary, Laxation Diary , and Nausea/Vomiting Diary daily for 2 days.

Arms: arm 1: Study drug, Lazanda, will be self-administered intranasally during this study. The dose of Lazanda is not predicted from the daily maintenance dose of opioid used to manage persistent cancer pain and must be determined by dose titration. The minimal effective intranasal dose from the radiation therapy simulation will be the dose used as pre-medication prior to any further radiation therapy fractions (up to 10 fractions).

Lazanda should be administered 15 (T-15) minutes prior to laying on the hard surface for each simulation visit. If the response to the titrated Lazanda dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained as deemed by the investigator.
Interventions: intervention 1: Lazanda
Intervention descriptions: intervention 1: Lazanda is supplied in glass bottles, containing 8 sprays of 100 mcL containing 100 mcg/100 mcL or 400 mcg/100 mcL concentration solution.

Protocol documents:
Prot_SAP_000.pdf: 
UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 1 of 53 
Protocol Date 03/19/2018 
 
 
 
 
Phase II, Open-Label Study to Evaluate Lazanda in Cancer Patients Receiving  
Palliative Radiation 
 
 
Principal Investigator 
Eric Roeland, MD 
Assistant Clinical Professor 
Department of Medicine 
Oncology & Palliative Care 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: 858-534-3361 
Fax: 858-822-5380 
E-mail: eroeland@ucsd.edu 
 
Co-Investigators 
James Murphy, MD, MS 
Daniel Simpson, MD 
Radiation Oncology 
 
Study Agent:  
Fentanyl nasal spray, Lazanda® 
 
IND Number:  
Exempt 
 
 
 
 
Protocol 
Date 
Original (v 1.0) 
4/18/2016 
Amendment 1 (v 2.0) 
10/06/2016 
Amendment 2 (V 3.0) 
12/29/2016 
Amendment 3 (V 4.0) 
04/03/2017 
Amendment 4 (V 5.0) 
06/11/2017 
Amendment 5 (V 6.0) 
09/18/2017 
Amendment 6 (V 7.0) 
03/19/2018 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 2 of 53 
Protocol Date 03/19/2018 
LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATOR 
Eric Roeland, MD 
University of California, San Diego 
Moores Cancer Center  
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Ph: 858-534-3361 
F: 858-822-5380 
eroeland@ucsd.edu 
 
 
BIOSTATISTICIANS 
Jiayi Hou, Ph.D. 
Clinical and Translational Research Institute (CTRI) 
University of California, San Diego  
9500 Gillman Drive #0990  
La Jolla, CA 92093-0990 
jhou@ucsd.edu 
 
Gordon Honerkamp-Smith, C.Phil.  
Clinical and Translational Research Institute (CTRI) 
University of California, San Diego  
9500 Gillman Drive #0990  
La Jolla, CA 92093-0990  
ghonerka@ucsd.edu 
 
Acknowledgements: 
The CTRI is partially supported by the National Institutes of Health, Grant UL1TR001442 of 
CTSA funding. 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 3 of 53 
Protocol Date 03/19/2018 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
UCSD Principal Investigator 
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 4 of 53 
Protocol Date 03/19/2018 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS.......................................................................................................................... 7 
STUDY SCHEMA ......................................................................................................................................... 9 
STUDY SUMMARY .................................................................................................................................... 10 
1.0 
BACKGROUND AND RATIONALE ........................................................................................... 14 
1.1 
Disease Background ................................................................................................................... 14 
1.2 
Study Agent(s) ............................................................................................................................ 16 
1.3 
Rationale ..................................................................................................................................... 17 
2.0 
STUDY OBJECTIVES ................................................................................................................ 17 
2.1 
Primary Objectives ...................................................................................................................... 17 
2.2 
Secondary Objectives ................................................................................................................. 17 
2.3 
Exploratory Objectives ................................................................................................................ 17 
2.4 
Endpoints .................................................................................................................................... 18 
3.0 
PATIENT ELIGIBILITY ............................................................................................................... 18 
3.1 
Inclusion Criteria ......................................................................................................................... 18 
3.2 
Exclusion Criteria ........................................................................................................................ 19 
4.0 
TREATMENT PLAN ................................................................................................................... 19 
4.1 
Study Design ............................................................................................................................... 19 
4.2 
Treatment Dosage and Administration ....................................................................................... 21 
4.2.1 
Radiation Simulation Visit(s) 22 
4.2.2 
Radiation Treatment Visits 
23 
4.3 
Pre-Medications .......................................................................................................................... 24 
4.4 
Permitted concomitant therapy ................................................................................................... 24 
4.5 
Prohibited concomitant therapy .................................................................................................. 24 
4.6 
Radiation Therapy ....................................................................................................................... 24 
4.7 
Toxicities and Dosing Delays/Dose Modifications ...................................................................... 24 
4.8 
Duration of Study Treatment ....................................................................................................... 25 
4.9 
Duration of Follow Up ................................................................................................................. 26 
4.10 
Discontinuation from Study Participation .................................................................................... 26 
5.0 
STUDY PROCEDURES ............................................................................................................. 26 
5.1 
Definitions of Study Assessments .............................................................................................. 26 
5.1.1 
Medical history 
26 
5.1.2 
Demographics 
26 
5.1.3 
Review subject eligibility criteria 
26 
5.1.4 
Concomitant medications 
27 
5.1.5 
Physical exam 
27 
5.1.6 
Vital signs and weight 
27 
5.1.7 
Performance status 27 
5.1.8 
Adverse event assessment 27 
5.1.9 
Serum chemistries 
27 
5.1.10 
Pregnancy test (for females of child bearing potential) 27 
5.1.11 
Patient-Reported Measures 27 
5.2 
Screening/Baseline Procedures.................................................................................................. 29 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 5 of 53 
Protocol Date 03/19/2018 
5.3 
Procedures During Treatment..................................................................................................... 30 
5.3.1 
Radiation Therapy Simulation 
30 
5.3.2 
Radiation Therapy (Hypofractionation) 
30 
5.4 
Follow-up Procedures ................................................................................................................. 30 
6.0 
MEASUREMENT OF EFFECT ................................................................................................... 31 
6.1 
Safety/tolerability ......................................................................................................................... 31 
6.2 
Efficacy assessment ................................................................................................................... 31 
7.0 
ADVERSE EVENTS ................................................................................................................... 31 
7.1 
Adverse Event Monitoring ........................................................................................................... 31 
7.2 
Severity ....................................................................................................................................... 32 
7.3 
Seriousness ................................................................................................................................ 32 
7.4 
Relationship ................................................................................................................................ 33 
7.5 
Prior experience .......................................................................................................................... 33 
7.6 
Reporting Requirements for Adverse Events ............................................................................. 33 
7.6.1 
Expedited Reporting 33 
7.6.2 
Routine Reporting Requirements 
34 
7.6.3 
Pregnancy Reporting Requirements 34 
8.0 
AGENT INFORMATION ............................................................................................................. 34 
8.1 
Lazanda® ..................................................................................................................................... 34 
8.1.1 
Return and Retention of Study Drug 36 
8.1.2 
Drug Accountability/Subject Compliance 
36 
9.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 36 
9.1 
Study Design/Study Endpoints ................................................................................................... 36 
9.2 
Sample Size and Accrual ............................................................................................................ 36 
9.3 
Data Analyses Plans ................................................................................................................... 37 
9.3.1 
Primary Analysis 
37 
9.3.2 
Safety Endpoint 
37 
9.3.3 
Secondary Analyses 37 
9.3.4 
Exploratory Analyses 
37 
10.0 
STUDY MANAGEMENT ............................................................................................................. 38 
10.1 
Conflict of Interest ....................................................................................................................... 38 
10.2 
Institutional Review Board (IRB) Approval and Consent ............................................................ 38 
10.3 
Registration Procedures ............................................................................................................. 38 
10.4 
Data Collection and Management .............................................................................................. 38 
10.5 
Subject Data Protection .............................................................................................................. 39 
10.6 
Data and Safety Monitoring/Auditing .......................................................................................... 39 
10.7 
Adherence to the Protocol .......................................................................................................... 39 
10.8 
Emergency Modifications ............................................................................................................ 39 
10.9 
Protocol Violations ...................................................................................................................... 40 
10.10 
Amendments to the Protocol ................................................................................................... 40 
10.11 
Record Retention .................................................................................................................... 40 
10.12 
Obligations of Investigators ..................................................................................................... 40 
   10.13     Data Reporting………………………………………………………………………………………....42 
11.0 
REFERENCES ............................................................................................................................. 2 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 6 of 53 
Protocol Date 03/19/2018 
12.0 
APPENDICES ............................................................................................................................. 42 
Appendix B. Strong and Moderate CYP3A4 Inhibitors ........................................................................... 44 
Appendix C. Numerical Rating Score (NRS) for Pain ............................................................................. 45 
Appendix D. Brief Pain Inventory-short form (BPI-sf) ............................................................................. 46 
Appendix E. Medication Use Diary.......................................................................................................... 48 
Appendix F. Laxation Diary ..................................................................................................................... 49 
Appendix G. Nausea/Vomiting Diary....................................................................................................... 50 
Appendix H. Study Drug Diary ................................................................................................................ 51 
Appendix I. NRS Scale Log ..................................................................................................................... 52 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 7 of 53 
Protocol Date 03/19/2018 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine transaminase 
AST 
Aspartate Transaminase 
BPI-sf 
Brief Pain Inventory-short form 
BTCP 
Breakthrough Cancer Pain 
BUN 
Blood Urea Nitrogen 
cGy 
Centigray 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRI 
Clinical and Translational Research Institute 
CURES 
Controlled Substance Utilization Review and Evaluation 
System 
CYP 
Cytochrome P450 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protections Program 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Services 
IQR 
Interquartile Range 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IMRT 
Intensity Modulated Radiation Therapy 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NRS 
Numerical rating system 
NSAID 
Non-steroidal Anti-inflammatory Drug 
ORT 
Opioid Risk Tool 
PDMP 
Prescription Drug Monitoring Program 
PI 
Pain Intensity 
PID 
Pain Intensity Difference 
prn 
As needed 
REMS 
Risk Evaluation and Management Strategy 
RT 
Radiation Therapy 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 8 of 53 
Protocol Date 03/19/2018 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Standard Deviation 
SPID 
Sum of Pain Intensity Differences 
SRS 
Stereotactic Radiosurgery 
TIRF 
Transmucosal Immediate-Release Fentanyl 
Tmax 
Time to Maximum Concentration 
UPR 
Unanticipated Problems involving Risk to subjects or 
others 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 9 of 53 
Protocol Date 03/19/2018 
STUDY SCHEMA 
 
 
 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 10 of 53 
Protocol Date 03/19/2018 
STUDY SUMMARY 
Title 
Phase II, Open-Label Study to Evaluate Lazanda in Cancer 
Patients Receiving Palliative Radiation 
Short Title 
Lazanda for Cancer Pain with Palliative Radiation 
Phase 
Phase II 
Methodology 
Single-center, open-label case series study  
Study Duration 
The anticipated total duration of this study is 1 year. Individual 
subject participation is limited to approximately 4-5 weeks. 
Study Center(s) 
University of California, San Diego (UCSD) Moores Cancer Center 
UCSD Medical Center - La Jolla 
Objectives 
Primary Objective 
Our primary objective is to assess the change in patient reported 
positional pain intensity (PI) as measured by an 11-point numerical 
rating scale (NRS-11) in cancer patients with bone metastases 
assessed at each daily palliative radiation fraction. Our primary 
objective will be measured using the pain intensity difference (PID) 
of the NRS-11 from baseline to 15-minutes post administration 
(PID15= PI0- PI15). 
 
Secondary Objectives 
Our secondary objectives are to: 
1) Assess change, baseline to 15 minutes, in patient reported pain 
severity using the Brief Pain Inventory Short Form (BPI-sf).1  
2) Evaluate adverse effects associated with Lazanda use utilizing 
the NCI CTCAE version 4.03 before and after palliative radiation. 
3) Contribute to the body of knowledge to improve patient care 
measures that address discomfort associated with radiotherapy for 
patients with bone metastases.  
 
Exploratory Objective 
To assess the impact on radiation treatment delivery efficiency.  
This will be quantified by determining the total time of radiation 
treatment. 
Number of Subjects 
6 
Diagnosis and Main 
Inclusion Criteria 
Patients with a pathologically-confirmed solid tumor or hematologic 
malignancy with symptomatic bone metastases.    
 
Key Inclusion Criteria: 
1. Patient is planned to receive hypofractionated palliative 
radiation ≤ 10 fractions.  
2. Patient must be opioid-tolerant (≥60mg morphine or equivalent) 
and on a stable dose of oral opioids for ≥ 1 week. Stable 
baseline opioid dosage defined as a dosage that does not 
fluctuate by > 50% from the average dosage over one week 
prior to screening. 
3. Patient must be on a stable dose of adjuvant pain therapies for 
one week prior to screening or after 4-5 half-lives of adjuvant 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 11 of 53 
Protocol Date 03/19/2018 
pain therapies (i.e., glucocorticoids, NSAIDs, anticonvulsants, 
pharmaceutical cannabinoids, tricyclic antidepressants). 
4. Patient is ≥ 18 years of age. 
5. ECOG Performance Status ≤ 3  
6. Negative pregnancy test prior to initiating study treatment for 
females of childbearing potential. 
 
Key Exclusion Criteria 
1. Patient is currently receiving or has received another 
investigational agent within 30 days or monoamine oxidase 
inhibitor within 14 days prior to study drug administration. 
2. Patients who require immobilization with a thermoplastic mask 
for radiation treatment. 
3. Patient is planned to receive interventional procedures (i.e., 
surgery) that may affect study outcomes. 
4. Patient has a history of hypersensitivity to fentanyl or opioids.  
5. Patient is pregnant or nursing.  
6. Patient is being treated with oxymetazoline for allergic rhinitis 
or has a disorder or current medication use likely to adversely 
affect normal functioning of the nasel mucosa. 
7. Patient has uncontrolled or rapidly escalating background pain.  
8. Patient has bradyarrhythmia. 
9. Patient is medically unstable. 
10. Patient is thought to be at risk for misuse, abuse, addiction or 
overdose for Schedule II controlled substance, as evidenced 
by an Opioid Risk Tool (ORT)2 score ≥ 8 and review of the 
California Prescription Control Monitoring Program (PDMP) 
Controlled Substance Utilization Review and Evaluation 
System (CURES) report demonstrates multiple prescribing 
providers and/or multiple pharmacies in the last 30 days.  
Study Product(s), Dose, 
Route, Regimen 
Lazanda (fentanyl) nasal spray is supplied as a 5-mL bottle 
containing 8 sprays of 100 mcL of solution containing either 100 
mcg or 400 mcg fentanyl base. Lazanda will be self-administered 
intranasally by subjects participating in this study. Subjects will 
undergo dose titration with Lazanda to determine the minimum 
effective and tolerable dose during their radiation simulation visit. 
This dose will be used as pre-medication prior to any further 
radiation therapy.  
Duration of 
administration 
Subjects will receive Lazanda at their radiation simulation visit and 
again as pre-medication prior to each radiation treatment (fraction), 
for an estimated treatment period of 10 days based on the patient’s 
radiation treatment plan.  
Statistical Methodology 
Descriptive statistics will be used to characterize overall pain 
change (base to 15) and pain change (base to 15) per treatment 
day (1,…,n). 
 
To analyze our secondary aim, change in our secondary aim, 
change in patient reported pain severity; we will use the BPI-sf. 
The BPI-sf will be used to calculate "worst pain” (calculated as the 
arithmetic mean of the four severity items measuring pain severity 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 12 of 53 
Protocol Date 03/19/2018 
in the BPI-sf). We will assess changes in BPI-sf using the same 
approach as our primary aim. Namely, change in BPI-sf “worst 
pain” score will be analyzed using a linear mixed-effects model to 
account for the repeated daily dosing. Modeling the difference in 
BPI-sf from baseline and 15 minutes at each fractionation visit; 
with a fixed effect for time and a subject level random intercept to 
account for within-patient variability. Descriptive statistics will be 
provided for overall pain severity change and pain severity change 
at each treatment day (1,…,n). As part of our secondary aim we 
will also provide descriptive statistics for adverse effects 
associated with Lazanda use utilizing the NCI CTCAE version 4.03 
stratified as before and after palliative radiation. 
 
Our exploratory aim will assess the impact of Lazanda on 
treatment delivery efficiency. This will be assessed by comparing 
treatment delivery efficiency in the Lazanda treated patients to the 
historic average. To assess this we will quantify each subjects 
average total time on the treatment table (averaged across each 
subjects fractionation visits, in minutes). This average will be 
compared to the clinic’s historic average of 6 minutes using a one-
sample t-test of the null hypothesis that the average time on the 
treatment table for Lazanda study patients equals 6 minutes. As a 
further exploratory aim we will also consider the effects of baseline 
pain intensity score, 24-hour opioid use (oral morphine 
equivalents) and total treatment time at each fraction (minutes) on 
change in pain intensity (PID15) by including each of them as fixed 
effects in the linear mixed-effects models.  
This trial will enroll approximately 6 subjects meeting the eligibility 
criteria described above. Conservatively assuming a 10% drop out 
rate, this will leave an analytic sample size of 5.  
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 13 of 53 
Protocol Date 03/19/2018 
SCHEDULE OF EVENTS 
 
Screening 
(<21 days from 
baseline) 
Radiation 
Therapy 
Simulation7  
(<14 days RT) 
Radiation Fraction  
(Daily, up to 10 
fractions) 
Post Treatment 
Follow-Up 
(Daily, for 2 
days) 
Informed consent 
X 
 
 
Medical and surgical history 
X 
 
 
Demographics 
X 
 
 
Eligibility criteria 
X 
 
 
ECOG Performance status 
X 
X 
X 
 
Document location of bone lesion 
X 
 
 
Pregnancy test (if applicable)1 
X 
 
 
Physical exam 
X 
Per routine care frequency 
Vital signs 
X 
 
Per routine care 
frequency 
Per routine care frequency 
Weight 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
Adverse events 
X 
X 
X4 
Comprehensive metabolic panel  
X5 
Per routine care frequency 
Record baseline 24-hour opioid dose 
X 
 
 
Record total time in radiation therapy unit 
X 
X 
 
Record recumbent time 
X 
X 
 
Lazanda dispensing & administration 
X6 
X6 
 
Radiation Therapy (hypofractionation) 
 
X 
 
Study drug diary 
X 
X 
 
Brief Pain Inventory Short Form 
X 
X 
X 
X 
Numerical Rating System Pain Score2 
 
X 
X 
X 
Patient medication use diary3 
X 
X 
X 
X 
Patient nausea/vomiting diary 
 
X 
X 
X 
Patient laxation diary 
 
X 
X 
X 
 
1) 
Females of childbearing potential only; must be performed within 72 hours of baseline. 
2) 
NRS Pain Score will be collected at a total 2 events: (1) radiation therapy simulation, and (2) at each radiation fraction (up to 10 fractions total). At each event, NRS 
pain scores will be recorded at T-15 (15 minutes prior to laying down on treatment surface), T0 minutes (laying down on treatment surface), and T+15 after laying 
down on the treatment surface.(Appendix I- NRS Scale log) 
3) 
To include a record of any anticancer therapy, vitamins, homeopathic/herbal remedies, nutritional supplements, opioid medication use, over-the-counter analgesics, 
and all other over-the-counter and PO medication use. 
4) 
Patients will be monitored for adverse events until 30 days following the last study drug administration. 
5) 
Serum chemistries performed within six weeks of baseline may be used to fulfill screening requirements. 
6) 
Lazanda will be self-administered by the subject 15 minutes (+ 5 minutes) prior to laying on the hard surface. 
7) 
If the 100-mcg dose does not achieve adequate pain control at the first assessment of the simulation visit, the subject will receive a second dose 2 hours later as per 
label until the optimal dose is obtained. If not practical the subject will delay or reschedule the next assessment of the simulation (within a 14 days period) or XRT 
delivery. 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 14 of 53 
Protocol Date 03/19/2018 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
1.1.1. Breakthrough Cancer Pain and Use of Opioids  
Pain is one of the most common symptoms for cancer patients. A subtype of pain is 
breakthrough cancer pain (BTCP), which is generally considered as any transitory pain 
experienced while a cancer patient has a controlled baseline pain management regimen in 
place.3 The time course of BTCP is characterized by a rapid onset of intense pain with a 
maximum intensity occurring around 15 minutes, followed by a short duration (median ~60 
minutes) or plateau period.4,5 The prevalence of cancer patients presenting with pain ranges 
from 30-40% at the time of diagnosis and increases up to 70-90% in advanced stages.6 The 
etiology of cancer pain can be attributed to the tumor itself as well as to treatments such as 
surgery, chemotherapy, or radiation.  
 
Opioids are used to treat moderate to severe BTCP and are considered the highest, “Step 3,” 
level of pain management by the World Health Organization.7 Oral short-acting opioids (e.g. 
morphine immediate-release [IR], oxycodone IR, and hydromorphone) have an estimated onset 
of action of 30-45 minutes and duration of effect of 3-6 hours. Even though the onset of action is 
quicker with short-acting opioids compared to long-acting opioids, 30-45 minutes may be too 
prolonged when experiencing BTCP. During a BTCP episode, parental opioids may be needed. 
An alternative to parental opioids and/or short-acting opioids for BTCP treatment is 
transmucosal immediate-release fentanyl (TIRF), such as a pectin-based nasal spray. In 
contrast to oral short-acting opioids, TIRFs have an immediate onset of action within minutes 
and duration of action of 1-2 hours. The onset of action and duration of action for a pectin-based 
nasal spray associates well with the time course of BTCP 5,8.  
 
1.1.2. Radiation Therapy 
 
Radiation therapy, also called radiotherapy, X-ray therapy or irradiation, uses high doses of 
radiation energy to destroy or damage cancer cells. Radiation breaks down DNA inside cancer 
cells, reducing cell growth by restricting cell division. Although surrounding normal cells may be 
affected by radiation, most healthy cells recover and resume their regular functions. Unlike 
chemotherapy, which exposes the entire body to cancer-directed therapy, radiation therapy is a 
localized treatment. Radiation therapy is a common treatment for many types of cancer.  
 
There are two main types of radiation therapy: external beam radiation therapy and internal 
beam therapy (brachytherapy). External beam radiation therapy is the most widely used type of 
radiation therapy, and can be used to treat large areas of the body. Palliative radiation therapy 
is typically delivered using 3-dimensional conformal radiotherapy (3DCRT) to direct radiation 
therapy towards at tumors while minimizing exposure to sensitive normal structures near the 
tumor in order to avoid treatment-related side effects. Palliative radiation treatments average 
6 minutes, usually last 15 minutes or less, and are completed once a day, five days a 
week, up to 10 days in duration.  
 
Advanced cancer patients often require palliative radiotherapy to treat cancer-related 
symptoms. A total dose of safe and effective radiotherapy is determined quantified in centigray 
(cGy) and this total dose is delivered over several treatments called fractions. Palliative radiation 
therapy regimens are typically delivered in daily doses of 300-800 cGy per day. This approach 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 15 of 53 
Protocol Date 03/19/2018 
is also known as hypofractionation. Precise delivery of radiation requires patients to lie still on a 
hard, flat surface that can result in significant acute pain, especially in the setting of painful bone 
metastases. 
 
 
Figure 1: Pain spinal metastases 
on CT scan. 
Figure 2: Patient in recumbent 
position during radiation therapy 
 
Radiation Oncology at UCSD 
UCSD Moores Cancer Center offers a comprehensive radiation oncology center with advanced 
radiation therapy services available, including:  
• 
External beam radiation, which 3DCRT, intensity-modulated radiation therapy, image-
guide radiation therapy, and volumetric-modulated arc therapy 
• 
Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) 
• 
Brachytherapy (internal radiation therapy) 
• 
Proton therapy 
 
Radiation therapy is a five-step process: 
1) During consultation, the patient meets with a physician and other members of the radiation 
oncology team to discuss best treatment options. 
2) A CT simulation is the most accurate way to precisely define the radiation treatment area. 
Simulation will determine a patient’s proper positioning on the treatment table that will be 
used throughout the course of treatment. Customized immobilization devices (to help 
patients remain still during treatments) are often created during simulation sessions. Small 
tattoos may be used to ensure proper alignment and treatment delivery.  
3) Using information from the CT simulation, dosimetrists work with the radiation oncologist 
and medical physicist to develop a treatment plan, which includes a total radiation dose 
(cGy), consideration of minimizing exposure to healthy tissue, and the number of fractions. 
4) Radiation Treatment usually begins less than one week after the simulation appointment. 
Radiotherapy treatments are usually five days per week with the total number of fractions 
determined by the treating physician. At each appointment, a therapist will position the 
patient on the table exactly as they were at the time of simulation. 
5) Follow-up Care visits are intended to monitor patient progress and address any side 
effects. These appointments are generally scheduled at three or six-month intervals.  
 
The Radiation Oncology department, located at the UCSD La Jolla campus adjacent to the 
Moores Cancer Center, is comprised of a team of physicians and medical physicists with 
expertise in leading-edge treatments and technologies, including 11 radiation oncologists, 11 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 16 of 53 
Protocol Date 03/19/2018 
radiation nurses, 22 radiation therapists as well as social workers who specialize in radiation 
oncology. 
 
1.1.3. Treatment of Pain During Palliative Radiation  
Advanced cancer patients often require palliative radiotherapy to treat cancer-related 
symptoms. Precise delivery of radiation requires patients to lie still on a hard, flat surface, which 
can result in significant acute pain and/or BTCP, especially in the setting of painful bone 
metastases. Ideally, this acute treatment-related pain associated with lying on the radiation 
treatment table could be pretreated with a short-acting opioid with a rapid onset of action. The 
outpatient radiation oncology setting limits the use of parenteral opioids. Current care for most 
cancer patients receiving hypofractionated radiation is an oral opioid pre-medication, which 
again is characterized by a one-hour onset of action and duration of effect of 3-6 hours, which 
does not associate with the time course of BTCP. A fentanyl pectin-based nasal spray would be 
ideal in this cancer patient population to treat acute, episodic, BTCP pain and maximize 
radiation treatment delivery efficiency given its quick onset of action and convenient mode of 
delivery. 
1.2 
Study Agent(s) 
Fentanyl pectin nasal spray (Lazanda is commercially available and indicated for the 
management of BTCP in adults 18 years of age and older who are already receiving and who 
are tolerant to opioid therapy for treatment of cancer pain. Lazanda’s mechanism of action is a 
pure opioid agonist. Lazanda pharmacokinetics in healthy subjects and in patients with a history 
of allergic rhinitis have been published 9-11. In summary, median (range) time to maximum 
concentration (Tmax) is 15-30 (10.2-60) minutes. After single dose administration, maximum 
concentrations (Cmax) ranged from 0.3 to 1.74 ng/mL; elimination half-life is approximately 5.5 to 
9.7 hours. Fentanyl is metabolized in the liver and intestinal mucosa to norfentanyl by 
cytochrome P450 (CYP) 3A4. Concomitant use of Lazanda with a CYP3A4 inhibitor (Appendix 
B) may result in a potentially dangerous increase in fentanyl plasma concentrations, which 
could prolong adverse drug effects. Patients receiving Lazanda who begin or increase the dose 
of a CYP3A4 inhibitor drug should be carefully monitored for signs of opioid toxicity. More than 
90% of fentanyl is eliminated via biotransformation to N-dealkylated and hydroxylated inactive 
metabolites. The metabolites are mainly excreted in urine.  
 
In a randomized, double-blind, placebo controlled study, cancer patients (n=73) were titrated to 
an effective pain relief dose (100, 200, 400, or 800 mcg) of Lazanda. The sum of pain intensity 
difference at 30 minutes (SPID30) was 6.57 ± 4.99 (mean ± SD) and 4.45 ± 5.51 for Lazanda 
versus placebo, respectively (p<0.05). Other secondary pain measures including pain intensity 
(PI) scores, pain intensity difference (PID), and pain relief were all statistically significant 
compared to placebo at 10, 15, 30, 45, and 60 minutes after administration. Decreases in pain 
intensity by 2 or more were seen in 49% and 63% of patients 15 and 30 minutes after fentanyl 
pectin nasal spray administration.12 These results, specifically a statistically significant higher 
SPID and decreased pain intensity, are consistent in another randomized, placebo controlled, 
study in cancer patients (n=83).13  
 
In comparison to morphine sulfate IR, higher PID scores and a greater proportion of patients 
achieving >33% or >2 point pain intensity score reduction have been reported with 
Lazanda®.14,15 In one study, pain intensity difference at 15 minutes (mean ± SD) was 3.0 ± 0.2 
and 2.7 ± 0.2 (p<0.05) for Lazanda and morphine sulfate IR, respectively.15 Decreases in pain 
intensity by 2 or more was seen in 52.4% and 45.4% of patients (p<0.05) 10 minutes after 
Lazanda and morphine sulfate IR administration.14 In another study, PI scores after 5 minutes 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 17 of 53 
Protocol Date 03/19/2018 
(5.6 vs. 5.8) and after 20 minutes (3 vs 3.4) were significantly lower for Lazanda versus 
intranasal fentanyl. Five minutes after administration, more patients experienced a >33% pain 
intensity reduction (~13% vs. <5%; p<0.05), while at 20 minutes after administration, more 
patients experiences a >50% pain intensity reduction (~71% vs. ~55%; p<0.05) with Lazanda.16  
 
Common adverse events are drowsiness, nausea, vomiting, and constipation, with most these 
symptoms mild to moderate in severity. Nasal symptoms, including obstruction, discomfort, 
itching, sneezing, dryness, and crusting have also been mostly reported as mild and moderate 
in severity.12-17 Ninety-nine serious adverse events have been reported in 3 studies, with 25 of 
these deemed related to fentanyl pectin nasal spray.12,15,17 Two deaths possibly related to 
fentanyl pectin nasal spray have been reported.15,17. In one death, the patient developed 
cyanosis, loss of consciousness, and upper airway obstruction after an apparent unintentional 
overdose during a breakthrough pain episode.17 
 
The initial starting dose for this study will be Lazanda 100 mcg prior to radiation therapy 
simulation. A 100 mcg dose is the initial dose of Lazanda for all patients as detailed in the 
product package insert. Lazanda dose titration will follow the guidelines as indicated in the 
product package insert from the baseline visit through the end of radiation therapy. If the subject 
does not experience relief after 30 minutes, he or she may take another 100 mcg but must wait 
at least 2 hours from the first spray before administering this second 100 mcg dose.  
1.3 
Rationale 
Precise delivery of radiation requires patients to lie still on a hard, flat surface which can result in 
significant acute pain and/or BTCP, especially in the setting of painful bone metastases. Ideally, 
this acute treatment-related pain associated with lying on the radiation treatment table could be 
pretreated with a short-acting opioid with a rapid onset of action. Currently most cancer patients 
receiving hypofractionated radiation are limited to oral opioid pre-medication characterized by a 
one-hour onset of action and a half-life of four hours which does not associate with the time 
course of BTCP. Pain medication delivered via an intranasal route would be ideal in this cancer 
patient population to treat acute, episodic BTCP pain and maximize radiation treatment delivery 
efficiency given its quick onset of action and convenient mode of delivery. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
Our primary objective is to assess the change in patient reported positional pain intensity (PI) as 
measured by an 11-point numerical rating scale (NRS-11) in cancer patients with bone 
metastases assessed at each daily palliative radiation fraction. Our primary objective will be 
measured using the pain intensity difference (PID) of the NRS-11 between 0 minutes and 15 
minutes after laying down on the hard surface (PID15= PI0- PI15).  
2.2 
Secondary Objectives  
1. To assess change in patient reported pain severity using the Brief Pain Inventory 
Short Form (BPI-sf).1 
2. To evaluate adverse effects associated with Lazanda use utilizing the NCI CTCAE 
version 4.03 before and after palliative radiation 
2.3 
Exploratory Objectives 
1. To assess the impact on radiation treatment delivery efficiency.  This will be 
quantified by determining the total radiation treatment time. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 18 of 53 
Protocol Date 03/19/2018 
2. To examine the effect of baseline pain intensity score, 24-hour opioid use (oral 
morphine equivalents) and total treatment time at each fraction (minutes) on change 
in pain intensity (PID15) 
2.4 
Endpoints 
The primary endpoint on this study is change in positional pain intensity as measured by NRS-
11 pain scores (Appendix C) (PID15= PI0- PI15). Change in NRS-11 pain scores will be 
calculated from the time of laying down on the hard surface (0 minutes) to the 15-minute time 
point. NRS-11 (at time 0 and time 15) will be collected at the radiation simulation and at each 
subsequent radiation therapy visit. The rationale for obtaining a PID at 15 minutes, is based on 
the reported intranasal fentanyl Cmax of 15-30 min. 
 
Secondary endpoints include pain severity difference as measured by the Brief Pain Inventory 
Short Form (BPIsf)18 (Appendix D).We will compare the BPIsf pain scores from the time of 
laying down on the hard surface (0 minutes) to 15 minutes after laying down at each 
fractionation visit . As a secondary endpoint we will also examine Lazanda safety, defined as 
the rate of drug-related adverse events experienced assessed according to the NCI’s CTCAE 
v4.03 toxicity criteria. 
 
Exploratory endpoints will include total recumbent time at each fractionation visit,  measured in 
minutes. 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
 
1. Patient able to understand and the willingness to sign a written informed consent. 
2. Pathologically-confirmed solid tumor or hematologic malignancy with symptomatic bone 
metastases. 
3. Patient is planned to receive hypofractionated palliative radiation ≤ 10 fractions.  
4. Patient must be opioid-tolerant (greater than or equal to 60mg morphine or equivalent) 
and on a stable dose of oral opioids for greater than or equal to 1 week. Stable baseline 
opioid dosage defined as a dosage that does not fluctuate by more than 50% from the 
average dosage over one week prior to screening. 
5. Patient must be on a stable dose of adjuvant pain therapies for one week prior to 
screening or after 4-5 half-lives of adjuvant pain therapies (i.e., glucocorticoids, NSAIDs, 
anticonvulsants, pharmaceutical cannabinoids, tricyclic antidepressants). 
6. Patient is ≥ 18 years of age. 
7. Both men and women of all races and ethnic groups are eligible for this trial. 
8. ECOG Performance Status ≤ 3 (see Appendix A) 
9. Women of child-bearing potential and men with partners of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 28 days 
following completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
• 
A woman of child-bearing potential is any female (regardless of sexual orientation, 
having undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 19 of 53 
Protocol Date 03/19/2018 
o Has not undergone a hysterectomy or bilateral oophorectomy; or 
10. 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). Women of child-bearing 
potential has negative pregnancy test prior to initiating study drug dosing. 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Patient is currently receiving or has received another investigational agent within 30 days or 
monoamine oxidase inhibitor within 14 days prior to Lazanda administration. 
 
2. Patients who require immobilization with a thermoplastic mask for radiation treatment. 
 
3. Patient is planned to receive interventional procedures (i.e. surgery) that may affect study 
outcomes. 
 
4. Patient has a history of hypersensitivity to fentanyl or opioids.  
 
5. Patient is pregnant or nursing. There is a potential for congenital abnormalities and for this 
regimen to harm nursing infants. 
 
6. Patient is being treated with oxymetazoline for allergic rhinitis or has a disorder or current 
medication use likely to adversely affect normal functioning of the nasal mucosa. 
 
7. Patient has uncontrolled or rapidly escalating background pain.  
 
8. Patient has bradyarrhythmia.  
 
9. Patient is considered medically unstable. 
 
10. Patient is thought to be at risk for misuse, abuse, addiction or overdose for Schedule II 
controlled substance, as evidenced by the following: 
a. An Opioid Risk Tool (ORT) score of greater/less than or equal to 8.2  
b. A review of the California Prescription Control Monitoring Program (PDMP) Controlled 
Substance Utilization Review and Evaluation System (CURES) report demonstrates 
multiple prescribing providers and/or multiple pharmacies in the last 30 days. The 
CURES report will also be used to verify opioid use, opioid dose, and current 
prescribing providers.  
4.0 
TREATMENT PLAN 
4.1 
Study Design 
This is a phase II, single-center, open-label study. We anticipate recruitment of approximately 
15 total study participants at the UCSD Moores Cancer Center. Study participants will be 
recruited across all oncology disease teams. Potential participants will be identified in weekly 
palliative care or disease team patient triage meetings.  
 
To meet eligibility for participation, a patient must be greater than or equal to 18 years old, have 
histologically-confirmed cancer with symptomatic bone metastases, an ECOG performance 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 20 of 53 
Protocol Date 03/19/2018 
status less than or equal to 3, and are planned to receive hypofractionated palliative radiation 
less than or equal to 10 fractions. Qualifying subjects must be opioid-tolerant, defined as greater 
than or equal to 60mg morphine or equivalent, and be on a stable dose of oral opioids for 
greater than or equal to 1 week. Stable baseline opioid dosage is defined as a dosage that does 
not fluctuate by more than 50% from the average dosage over one week prior to screening. 
Patients must also be on a stable dose of adjuvant pain therapies for one week prior to 
screening or after 4-5 half-lives of adjuvant pain therapies. Patients will be excluded if they are 
receiving or have received another investigational agent within 30 days or monoamine oxidase 
inhibitor within 14 days prior to Lazanda administration, have known hypersensitivity to fentanyl 
or opioids, have known, planned interventional procedures such as surgery that may affect 
study outcomes, are pregnant or nursing, have a disorder or current medication use likely to 
adversely affect normal functioning of the nasal mucosa, have uncontrolled or rapidly escalating 
background pain, or are medically unstable. 
 
The primary objective of this study is to assess the change in patient reported positional pain 
intensity (PI) as measured by an 11-point numerical rating scale (NRS-11) (Appendix C) in 
cancer patients with bone metastases assessed at a simulation visit and each subsequent daily 
palliative radiation fraction. Our primary objective will be measured using the pain intensity 
difference (PID) of the NRS-11 from the time of laying down on the hard surface (0 minutes) to 
the 15 minutes after laying down on the hard surface timepoint at baseline (the simulation visit) 
and at each subsequent study visit (PID15= PI0- PI15). 
 
Secondary objectives will seek to assess patient reported pain severity using the BPI-sf 
(Appendix D), and evaluate adverse effects associated with Lazanda use utilizing the NCI 
CTCAE version 4.03 before and after palliative radiation. 
 
Exploratory objectives will assess the impact on radiation treatment delivery efficiency, which 
will be quantified by determining the total time of radiation treatment, defined as the average 
time on the treatment table for each fractionation visit. A second exploratory objective will be to 
examine the effect of: baseline pain intensity score, 24-hour opioid use (oral morphine 
equivalents) and total treatment time at each fraction (minutes) on change in pain intensity 
(PID15) 
   
 
After obtaining written informed consent, patients will have the following procedures completed 
to confirm eligibility: physical exam with vital signs and weight, ECOG performance status, 
comprehensive metabolic panel, and a serum pregnancy test (women of child-bearing potential 
only). During this screening period, patients will also complete a baseline NRS pain score and 
BPI-sf questionnaire (Appendix D), and report baseline 24-hour opioid dose. 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 21 of 53 
Protocol Date 03/19/2018 
Event 
NRS-11 
BPI-
sf 
Diaries 
 
 
 
Medication 
Use 
Nausea 
Vomiting 
Laxation 
Simulation 
T-15, T0, 
T+15 
T15+ 
X 
X 
X 
Daily radiation fraction 
T-15, T0, 
T+15 
T15+ 
X 
X 
X 
Table 1: Summary of Assessments; NRS-11 = numerical rating scale; BPI-sf = Brief Pain 
Inventory short form; T-15= 15 minutes prior; T0=at point of laying down; T+15 = 15 minutes 
after layind down; T15+ = any point after 15 minutes from laying down; X = once daily 
 
 
Simulation Evaluation 
The subject will then undergo radiation therapy simulation procedures (within approximately 2 
weeks of radiation therapy) followed by hypofractionated radiation therapy, according to UCSD 
Radiation Oncology standard procedure and treatment plan determined by the subject’s 
radiation oncologist. During radiation simulation and daily during each visit to the radiation 
center for hypofractionation delivery, subjects will have vital signs and weight collected per 
routine care. An ECOG performance status will also be assessed daily during radiation therapy. 
At the time of radiation simulation and daily during radiation therapy, subjects will complete the 
BPI-sf (Appendix D), Medication Use Diary (Appendix E), Laxation Diary (Appendix F), and 
Nausea/Vomiting Diary (Appendix G). NRS pain scores will also be collected at three time 
points during each visit to the radiation center: 15 minutes prior to laying on the hard surface (T-
15), at the time of laying on the hard surface (T0), and at 15 minutes after laying on the hard 
surface(T+15). Exact time of each pain score rating will also be collected. The study coordinator 
will record total time in radiation therapy unit and total recumbent time (time laying down) during 
the simulation and each radiation treatment visit. Additionally, radiation treatment parameters, 
the presence of any adverse effects (NCI CTCAE v 4.03), and concomitant medications will be 
recorded.  
 
Lazanda Dosing During Simulation 
Subjects will receive study drug, Lazanda at 100mcg dose, 15 minutes prior to simulation (T-15) 
at the radiation therapy simulation visit. Lazanda dose titration will follow the guidelines as 
indicated in the product package insert from the radiation simulation visit through the end of 
radiation therapy. Lazanda dose titration procedures are further detailed in Section 4.2.  
 
Subjects will undergo a post treatment follow-up period after completion of their radiation 
therapy. During this follow-up period, subjects will complete the BPI-sf (Appendix D), 
Medication Use Diary (Appendix E), Laxation Diary (Appendix F), and Nausea/Vomiting Diary 
(Appendix G) daily for 2 days. Concomitant medication use will also be recorded. Subjects will 
be monitored for the presence of any adverse effects (NCI CTCAE v 4.03) until 28 days 
following their last dose of Lazanda.  
4.2 
Treatment Dosage and Administration 
Study drug, Lazanda, will be self-administered intranasally during this study. The dose of 
Lazanda is not predicted from the daily maintenance dose of opioid used to manage persistent 
cancer pain and must be determined by dose titration. Due to differences in pharmacokinetic 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 22 of 53 
Protocol Date 03/19/2018 
properties and individual variability, do not switch patients on a mcg per mcg basis from any 
other fentanyl product as Lazanda is not equivalent with any other fentanyl product.  
 
4.2.1 Radiation Simulation Visit(s) 
To determine an individual patient’s effective and tolerable Lazanda dose, each subject will 
undergo dose titration during the radiation simulation visit. Lazanda dose for all subjects on 
study, including those switching from another fentanyl product, will be determined according to 
the following procedures:  
• 
15 minutes prior (T-15) to beginning the radiation therapy simulation, subjects will 
receive an initial dose of 100 mcg (1 spray) of Lazanda in one nostril prior to lying on the 
CT simulation hard surface. 
• 
If adequate analgesia is obtained within 30 minutes of administration of the 100-mcg 
single spray, subsequent pain episodes will be treated with this dose. 
• 
If the subject does not experience relief after 30 minutes, he or she may take another 
100 mcg in the opposite nostril but must wait at least 2 hours (i.e., T-15 + 2 hours) 
from the first spray before administering this second 100 mcg dose. The subject may 
delay or reschedule the simulation (within a 14 days period) or radiation delivery to 
achieve the adequate pain control dose. 
• 
If adequate analgesia is still not achieved, the subject will continue to dose escalate in a 
step-wise manner at a minimum of 2 hours between each subsequent escalation until 
adequate analgesia with tolerable side effects is achieved. A maximum of 4 doses or 
400 mcg allowed per day.  
• 
Dose titration steps are further detailed in Table 1. 
 
Table 1: Lazanda Dose Titration Steps 
 
Lazanda Dose 
Using 
100 mcg 
1 x 100 mcg spray 
200 mcg 
2 x 100 mcg spray (1 in each nostril) 
400 mcg 
4 x 100 mcg spray (2 in each nostril, alternate nostrils) or 1 x 400 mcg spray 
 
Each bottle contains a total of 8 sprays. Lazanda bottles come in 100 mcg or 400 mcg dose. If 
using dose of 100 mcg with the 100-mcg spray, the patient would have total of 8 doses in a 
single bottle. If using dose of 200 mcg with the 100-mcg spray, the patient would have total of 4 
doses in a single bottle. If using dose of 400 mcg with the 100-mcg spray, the patient would 
have total of 2 doses in a single bottle. Alternately, if using a bottle of the 400-mcg spray at a 
dose of 400 mcg, the patient would have total of 8 doses in a single bottle. 
 
Lazanda titration should be done with caution in patients with chronic obstructive pulmonary 
disease or preexisting medical conditions predisposing them to respiratory depression and in 
patients susceptible to intracranial effects of CO2 retention. Caution should also be used in 
patients on central nervous system (CNS) depressants and potent CYP3A4 inhibitors.  
 
The minimal effective intranasal dose from the radiation therapy simulation will be the dose 
used as pre-medication prior to any further radiation therapy fractions (up to 10 fractions). 
Lazanda should be administered 15 (T-15) minutes prior to laying on the hard surface for each 
simulation visit. If the response to the titrated Lazanda dose markedly changes, an adjustment 
of dose may be necessary to ensure that an appropriate dose is maintained as deemed by the 
investigator.  


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 23 of 53 
Protocol Date 03/19/2018 
 
Subjects will be instructed on the proper use of Lazanda as follows:  
1) Prime the device before use by spraying into the pouch (4 sprays in total). If study drug 
has not been used for 5 days, re-prime by spraying once. 
2) Insert the nozzle of the Lazanda bottle a short distance (about ½ inch) into the nose and 
point towards the bridge of the nose, tilting the bottle slightly.  
3) Press down firmly on the finger grips until hearing a “click” and the number in the 
counting window advances by one.  
 
Subjects will also be advised that the fine mist spray is not always felt on the nasal mucous 
membrane and to rely on the audible click and advancement of the dose counter to confirm a 
spray have been administered. 
 
 
4.2.2 Radiation Treatment Visits 
Lazanda will be self-administered by the subject while attending their visit to the radiation 
treatment center, and will be monitored closely by the clinic staff and study coordinator. 
Therefore, the chance for a missed dose is rare. However, should a subject miss a Lazanda 
dose prior to treatment fraction, he or she will be instructed to take the dose as soon as it is 
remembered on the same day prior to radiation.  
 
The dose used as pre-medication prior to any radiation therapy fractions is as described in the 
titration schema listed above in section 4.2.1 and described in Table 1. 
 
If a patient takes less than the minimal effective dose of Lazanda, they should be monitored 
closely for evidence of opioid withdrawal symptoms and reversal of central analgesic effects. In 
cases of known or suspected overdose, symptomatic treatment as well as monitoring of vital 
functions will be performed. In cases of severe intoxication, intensive care procedures will be 
completed. Close medical supervision and monitoring will be continued until the patient 
recovers.  
 
Subjects will be required to record each self-administered dose of Lazanda on a Study Drug 
Diary (Appendix H) from the time of the radiation simulation visit through the end of radiation 
therapy. Details of Lazanda administration, including date and time of administration as well as 
number of sprays administered and total daily dose will be recorded by the subject on the Study 
Drug Diary.  
 
Lazanda will be dispensed to the patient in nasal spray bottle format, within a child-resistant 
outer container. The child-resistant container should be opened just prior to initial product use.  
Subjects will be instructed to replace the bottle in the child-resistant container and out of reach 
of children between doses. Subjects will also be instructed to avoid consumption of grapefruit or 
grapefruit juice as this is a potent inhibitor of the CYP3A4 enzyme.  
 
There are additional no requirements for monitoring of vital signs or other parameters following 
Lazanda administration. Treatment with Lazanda does not require that any pre-treatment 
parameters be met prior to dispensing and/or administration. However, subjects will be advised 
not to drive during study participation and must be accompanied to all treatments. 
 
Any adverse events or serious adverse events resulting from known or suspected overdose will 
be reported according to instructions in Section 7.6 of the protocol. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 24 of 53 
Protocol Date 03/19/2018 
4.3 
Pre-Medications 
There are no required pre-medications on this study. 
4.4 
Permitted concomitant therapy 
Patients must remain on around-the-clock opioids when taking Lazanda. Throughout the study, 
many participants will be receiving a long-acting opioid for control of background pain and an 
immediate-release opioid as needed (“prn”) for breakthrough pain, although some may be 
receiving only a short-acting opioid on a scheduled basis. If the participant experiences more 
than 4 episodes of breakthrough pain per day while on study, the investigator will re-evaluate 
and appropriate titrate short and long-acting opioids per standard of care. Changes in the opioid 
regimen may be made to ensure appropriate pain control. Any changes to the maintenance 
opioid dosing regimen will be recorded. Concomitant non-opioid analgesics will be permitted, 
but investigators will be encouraged to maintain such drugs at stable doses on-study.  
 
Fentanyl is metabolized in the liver and intestinal mucosa to norfentanyl by CYP3A4. 
Concomitant use of Lazanda with a CYP3A4 inhibitor (Appendix B) may result in a potentially 
dangerous increase in fentanyl plasma concentrations, which could prolong adverse drug 
effects. Patients receiving Lazanda who begin or increase the dose of a CYP3A4 inhibitor drug 
is permitted, but should be carefully monitored for signs of opioid toxicity. 
 
Medications required to treat adverse events and manage cancer symptoms, concurrent stable 
disease (e.g., controlled hypertension) and supportive care agents such as erythropoietin, 
granulocyte growth factors, or blood transfusion, and pain medications are allowed. The patient 
needs to notify the investigational site about any new medications he/she takes after the start of 
the study medication. All medications (other than study drug) and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the patient starts 
treatment with study drug must be recorded in the patient’s medical record. 
 
Palliative and supportive care for disease-related symptoms, including pain medications, is 
permitted. Hematopoietic growth factors such as erythropoietin or G-CSF are allowed if clinically 
indicated only after the first 28 days of study treatment. Use of growth factors will follow NCCN 
guidelines. 
4.5 
Prohibited concomitant therapy 
Unless there is a need for urgent intervention, additional medication for pain control will not be 
allowed without prior approval from the principal investigator. This includes over-the-counter 
treatments for pain. Concomitant use of a monoamine oxidase inhibitor is prohibited. Other 
investigational therapies must not be used while the patient is on the study. If such agents are 
required for a patient then the patient must be discontinued from the treatment portion of the 
study. 
4.6 
Radiation Therapy 
Subjects will undergo radiation therapy simulation procedures and receive palliative radiation 
during this trial according to UCSD Radiation Oncology standard procedure, and according to 
the radiation treatment plan as determined by their radiation oncologist.  
 
4.7 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity according to the NCI CTCAE, version 4.03. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 25 of 53 
Protocol Date 03/19/2018 
Dose adjustments should be made according to the system showing the greatest degree of 
toxicity.  
 
Table 2: Dose Modifications for Lazanda-Related Nausea and/or Vomiting 
 
Nausea/Vomiting 
Management for Lazanda 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose. 
Grade 3 
Hold until < Grade 2. Resume at same dose. 
Grade 4 
Off protocol therapy 
Recommended symptom management: Treatment with a dopamine antagonist antiemetic (e.g. 
metoclopramide, prochlorperazine, haloperidol) and strong consideration of premedication prior to next 
Lazanda dose. 
 
Table 3: Dose Modifications for Lazanda-Related Constipation 
 
Constipation 
Management for Lazanda 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose. 
Grade 3 
Hold until < Grade 2. Resume at same dose. 
Grade 4 
Off protocol therapy 
Recommended symptom management: Opioid-induced constipation is managed with stimulant laxatives 
(senna, bisacodyl) with or without an osmotic laxative (e.g. polyethylene glycol). 
 
Table 4: Dose Modifications for Lazanda-Related Urinary Retention 
 
Urinary Retention 
Management for Lazanda 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose. 
Grade 3 
Hold until < Grade 2. Resume at same dose  
Grade 4 
Off protocol therapy 
Recommended symptom management: Evaluation including physical exam, ultrasound bladder scan, 
and consideration of a time-limited trial of catheter placement. 
 
Table 5: Dose Modifications for Lazanda-Related Somnolence 
 
Somnolence 
Management for Lazanda 
≤ Grade 1 
No action required. 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose. 
Grade 3 
Hold until < Grade 2. Resume at half dose. 
Grade 4 
Off protocol therapy 
Recommended symptom management: Urgent evaluation by investigator and medical management per 
standard of care. 
 
Patients requiring a delay of greater than 2 weeks or greater than 2 dose reductions in Lazanda 
dose for any toxicity should discontinue protocol therapy. 
4.8 
Duration of Study Treatment 
In the absence of treatment delays due to adverse events, treatment may continue up to a total 
approximately 4 weeks or until: 
• 
Inter-current illness or worsening of a medical condition that prevents further 
administration of treatment 
• 
Unacceptable adverse event(s) 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 26 of 53 
Protocol Date 03/19/2018 
• 
Rescue pain therapy for fails to palliative pain and/or the investigator believes that other 
treatment options may be more beneficial 
• 
The investigator believes that study treatment is jeopardizing patient safety 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
4.9 
Duration of Follow Up 
Patients will be followed daily for a 2-day period following the last study drug administration. 
During this period, data regarding ECOG performance status, 24-hour opioid use, number of 
daily bowel movements and nausea/vomiting episodes, concomitant medication use, and 
patient-reported outcomes will be collected. Patients will be followed for occurrence of adverse 
events for 28 days after completion of study treatment or until death, whichever occurs first. 
Patients removed from treatment for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  
4.10 
Discontinuation from Study Participation 
Patients may be removed from study participation at any time or at the discretion of the 
investigator for any of the following reasons: 
• 
The patient or legal representative withdraws consent for follow-up; 
• 
The patient is lost to follow-up; 
• 
The patient is unable to retain oral medication; 
• 
The patient dies; 
• 
The patient is non-compliant with study procedures; 
• 
The study is terminated 
 
Patients who are removed early from study participation will be asked to return all previously-
completed diaries and questionnaires and remaining study drug supply to a member of the 
study team. 
5.0 
STUDY PROCEDURES 
Refer to the study Schedule of Events for a list of study procedures and required time points. 
 
All patients will be closely monitored for safety and tolerability for the duration of study 
participation. 
5.1 
Definitions of Study Assessments 
5.1.1 Medical history 
A complete medical, surgical and oncology history as well as history of infections are 
obtained at screening. Any changes from Screening (e.g., worsening severity or 
abnormal findings) are considered to be adverse events (AEs). 
5.1.2 Demographics 
 Demographic profile will include date of birth, sex, patient-reported race, and ethnicity. 
5.1.3 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 will be completed to ensure subject 
qualification for study entry. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 27 of 53 
Protocol Date 03/19/2018 
 
5.1.4 Concomitant medications 
All concomitant therapy, including anticancer therapy, vitamins, homeopathic/herbal 
remedies, nutritional supplements, opioid medication use, over-the-counter analgesic 
medication use, and all other over-the-counter “prn” and oral medications, received by 
patients from 5 days prior to baseline until 2 days after the last study dose will be 
recorded in the patient’s medical record. If a reportable adverse event deemed related to 
study intervention (see Section 7) occurs within 28 days after last study dose and the 
patient has not started a new treatment, recording of concomitant medications related to 
the treatment of that adverse event should continue until resolution of the adverse event. 
5.1.5 Physical exam 
A complete physical examination should include the evaluation of general appearance; 
evaluation of head, eyes, ears, nose, and throat (HEENT); and cardiovascular, 
pulmonary, abdominal, musculoskeletal, skin, lymph nodes, neurological, and 
genitourinary systems. Subsequent exams may be targeted as appropriate. 
 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if 
clinically significant. 
5.1.6 Vital signs and weight  
Vital signs should include temperature, pulse, and blood pressure and weight.  
5.1.7 Performance status 
Performance status is evaluated by the by the ECOG scale (see Appendix A). 
5.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 7 for 
Adverse Event monitoring and reporting. 
5.1.9 Serum chemistries 
Comprehensive metabolic panel to include: albumin, alkaline phosphatase, total protein, 
ALT, AST, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, and total bilirubin. 
5.1.10 Pregnancy test (for females of child bearing potential) 
See section 3.1 for definition.  
5.1.11 Patient-Reported Measures 
All patient-reported measures will be completed via paper format, with materials 
provided to the patient by a study team member. A study member will provide initial 
training to the patient on how to complete study-required questionnaires and diaries. 
Patients are to complete the questionnaires and diaries in a quiet area, without 
assistance from family, friends or study team members. Patients must be able to read 
and comprehend the questionnaire in the language presented, and will be translated into 
foreign languages as needed for patient recruitment.  
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 28 of 53 
Protocol Date 03/19/2018 
 
5.1.11.1 Numerical Rating Score (NRS) Pain Score 
The NRS for pain is a unidimensional measure of pain intensity in adults (Appendix C). 
It is a segmented numeric version of the visual analog scale in which a respondent 
selects a whole number (0–10 integers) that best reflects the intensity of their pain. The 
common format is a horizontal bar or line. Similar to the pain visual analog scale, the 
NRS is anchored by terms describing pain severity extremes. Although various iterations 
exist, the most commonly used is the 11-item NRS.19 NRS Pain Score will be collected 
at a total of 2 events: CT simulation and on each day of radiation. At all time points 
where NRS pain scores are required, pain scores will be recorded: 15 min prior to laying 
on the hard surface (T-15), after laying on the hard surface (T0), and 15 min after laying 
down on the hard surface (T+15). This pain rating takes approximately 15 seconds to 
complete. 
 
5.1.11.2 Brief Pain Inventory-Short Form (BPI-sf) 
The Brief Pain Inventory (BPI) is one of the most widely used measurement tools for 
assessing clinical pain. The BPI allows patients to rate the severity of their pain and the 
degree to which their pain interferes with common dimensions of feeling and function. 
The BPI is available in two formats: the BPI-Short Form (BPI-sf), which is used for 
clinical trials, and the BPI-Long Form, which contains additional descriptive items that 
may be clinically useful. For the purposes of this study, we will use the BPI-sf, a 9-item 
self-administered questionnaire used to evaluate the severity of a patient's pain and the 
impact of this pain on the patient's daily functioning (Appendix D). The patient is asked 
to rate their worst, least, average, and current pain intensity, list current treatments and 
their perceived effectiveness, and rate the degree that pain interferes with general 
activity, mood, walking ability, normal work, relations with other persons, sleep, and 
enjoyment of life on a 10-point scale. The BPI-sf is validated for 24-hour recall. 
Participants will be asked to complete this questionnaire from baseline through the end 
of the post-treatment follow-up period. This questionnaire takes approximately 5 minutes 
to complete. 
 
5.1.11.3 Medication Use Diary 
Patients will complete a daily medication use diary as a record of all oral and self-
administered medications received from baseline through the end of the post-treatment 
follow-up period (Appendix E). This includes any anticancer therapy, vitamins, 
homeopathic/herbal remedies, nutritional supplements, opioid medication use, over-the-
counter analgesic medication use, and all other over-the-counter “as needed” (prn) and 
oral medications. A copy of the medication use diary will be collected from the patient by 
a member of the study team during each visit to clinic or the radiation treatment center, 
and entries will be recorded on the concomitant medications case report form. 
 
5.1.11.4 Laxation Diary 
Patients will complete a daily laxation diary as a record of the number of daily bowel 
movements from baseline through the end of the post-treatment follow-up period 
(Appendix F). Participants will be asked to complete this diary even on days where no 
daily bowel movement has occurred. A member of the study team will collect a copy of 
the diary from the patient during each visit to clinic or the radiation treatment center. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 29 of 53 
Protocol Date 03/19/2018 
 
5.1.11.5  Patient Nausea/Vomiting Diary 
Patients will complete a daily nausea/vomiting diary as a record of the number of daily 
nausea and vomiting episodes from baseline through the end of the post-treatment 
follow-up period (Appendix G). Participants will be asked to complete this diary even on 
days where no nausea or vomiting has occurred. A copy of the diary will be collected 
from the patient by a member of the study team during each visit to clinic or the radiation 
treatment center. 
 
5.1.11.6 Study Drug Diary  
Patients will complete a daily study drug diary (Appendix H) during the time that they 
are receiving Lazanda. Participants will be asked to complete this diary even on days 
when a Lazanda dose was missed or not taken. Details of Lazanda administration, 
including date and time of administration as well as number of sprays administered and 
total daily dose will be recorded. The study drug diary will be reviewed with the patient 
during each visit to clinic or the radiation treatment center, and a copy will be collected 
by a member of the study team. This diary will be used in combination with returned 
nasal spray bottles to support drug accountability.  
5.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 21 days prior to registration unless 
otherwise stated. The screening and baseline procedures include: 
• 
Written informed consent  
• 
Review of inclusion and exclusion criteria 
• 
Complete medical/oncology history 
• 
Demographics 
• 
Documentation of concomitant medications 
• 
Documentation of location(s) of bone lesion(s) 
• 
Complete physical examination, including vital signs and weight 
• 
ECOG performance status assessment 
• 
Comprehensive metabolic panel (serum chemistries performed within 6 weeks of 
baseline may be used to fulfill screening requirements) 
• 
Serum or urine pregnancy test (within 72 hours of Study Day 1) for females of child-
bearing potential (see inclusion/exclusion criteria) 
• 
Documentation of patient’s baseline 24-hour opioid dose 
• 
Collect single NRS pain score and time of NRS rating  
• 
BPI-sf 
 
Following confirmation of all eligibility criteria, subjects will be enrolled to the study through the 
Moores Cancer Center Clinical Trials Office. 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 30 of 53 
Protocol Date 03/19/2018 
 
5.3 
Procedures During Treatment 
During the radiation therapy simulation visit and throughout radiation therapy, physical exam 
and comprehensive metabolic panel will be performed per routine frequency for the participant’s 
oncology care. If these procedures are performed as part of routine oncology care, results will 
be collected for the study. 
 
5.3.1 Radiation Therapy Simulation 
The radiation therapy simulation visit will occur within approximately 14 days of the start of 
radiation therapy, as per standard radiation oncology protocol. Patients will have the following 
study procedures performed at the radiation simulation visit: 
• 
Documentation of concomitant medications and adverse events 
• 
Vital signs and weight per routine care 
• 
ECOG performance status assessment 
• 
Record total time in radiation therapy unit 
• 
Record recumbent time during radiation therapy 
• 
Lazanda dispensing and administration (see Section 4.2 for dose titration steps) 
• 
Collect NRS pain scores and time of NRS rating at: 15 minutes prior to laying on the 
hard surface, at the time of laying on the hard surface (0 minutes), and at 5, 10, 15 
minutes after laying on the hard surface  
• 
BPI-sf  
• 
Medication Use Diary (to be completed daily through the end of radiation therapy) 
• 
Nausea-Vomiting Diary (to be completed daily through the end of radiation therapy) 
• 
Laxation Diary (to be completed daily through the end of radiation therapy) 
 
5.3.2 Radiation Therapy (Hypofractionation)  
Patients will receive radiation therapy (hypofractionation) for a period of approximately 10 days 
(up to 10 fractions). Patients will have the following study procedures performed daily during 
radiation therapy: 
• 
Documentation of concomitant medications and adverse events 
• 
ECOG performance status assessment 
• 
Vital signs and weight per routine care 
• 
Record total time in radiation therapy unit 
• 
Record recumbent time during radiation therapy 
• 
Lazanda administration (see Section 4.2 for details of dosing) 
• 
Collect NRS pain scores and time of NRS rating at: 15 minutes prior to laying on the 
hard surface, at the time of laying on the hard surface (0 minutes), and at 5, 10, 15 
minutes after laying on the hard surface  
• 
BPI-sf 
• 
Medication Use Diary (to be completed daily through the end of radiation therapy) 
• 
Nausea-Vomiting Diary (to be completed daily through the end of radiation therapy) 
• 
Laxation Diary (to be completed daily through the end of radiation therapy) 
5.4 
Follow-up Procedures 
Patients will be followed for occurrence of adverse events for 30 days after the last dose of 
study drug or until death, whichever occurs first. Patients removed from treatment for 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 31 of 53 
Protocol Date 03/19/2018 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  
 
Patients will undergo a post-treatment follow-up period for 2 days following completion of 
radiation therapy. Patients will have the following study procedures performed daily for 2 days 
during the follow-up period: 
• 
Documentation of concomitant medications 
• 
Collect single NRS pain score and time of NRS rating 
• 
BPI-sf 
• 
Medication Use Diary 
• 
Nausea-Vomiting Diary 
• 
Laxation Diary 
 
Follow-up may consist of the study coordinator contacting the patient by telephone contact if no 
in-person standard oncology or radiation oncology visit is scheduled to occur during this time. 
 
Patients discontinuing study treatment prior to the end of the radiation therapy will undergo 
follow-up procedures for 2 days as described under Section 5.5.  
6.0 
Measurement of Effect 
6.1 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 4.03 (http://ctep.cancer.gov/reporting/ctc.html) for reporting of 
adverse events. Safety will be assessed from the time of informed consent through 30 days 
following the last dose of study drug.  
6.2 
Efficacy assessment  
The efficacy of treatment with Lazanda will be evaluated by NRS-11 pain scores and BPI-sf 
assessed from the baseline assessment through the end of the post-treatment follow-up period. 
For our primary aim, we will assess the pain intensity difference (PID) of the NRS-11 from the 
time of laying down on the hard surface (0 minutes) to the 15 minutes (T+15) after laying down 
on the hard surface timepoint at baseline and at each subsequent study visit (PID15= PI0- PI15).  
 
7.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
 
Progression of the cancer under study or events that are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 32 of 53 
Protocol Date 03/19/2018 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins at the time of informed consent signature and ends within 30 
days of the last administration of the study drug. 
 
All patients experiencing an adverse event, at least possibly related to the drug, will be 
monitored until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;  
• 
any clinically significant abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes observed; or 
• 
death. 
7.2 
Severity 
All adverse events will be graded according to the NCI CTCAE version 4.03. The CTCAE v4.03 
is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
• 
Fatal (grade 5): the event caused death. 
7.3 
Seriousness 
A “serious” adverse event (SAE) is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
2. Is life-threatening. The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization.  
Note: Hospitalization (including hospitalization for an elective procedure) for a pre-
existing condition that has not worsened does not constitute a serious adverse event. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event.  


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 33 of 53 
Protocol Date 03/19/2018 
• 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as SAE. 
The event may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
• 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
7.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.5 
Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed in the current known 
adverse events listed in the agent clinical experience section of this protocol and Lazanda 
prescribing information. 
7.6 
Reporting Requirements for Adverse Events 
7.6.1 Expedited Reporting 
A. The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the study drug.  
B. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 34 of 53 
Protocol Date 03/19/2018 
 
C. The FDA must be notified according to the following timelines: 
• 
within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and  
• 
within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 
3) at least possibly related to study participation. 
D. A copy of all SAEs will be submitted to Depomed’s safety designee using the approved 
local regulatory form within 24 hours of the Principal Investigator’s awareness by email 
(drugsafety@depomed.com) or fax (800-941-3742). 
 
7.6.2 Routine Reporting Requirements 
A. The UCSD HRPP must be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.  
 
B. The FDA must be notified of all non-serious adverse events annually 
at the time of the annual report. 
 
C. Depomed will be notified of all non-serious adverse events in 
summary or line-item form upon Depomed’s request and at the 
conclusion of the study.    
 
7.6.3 Pregnancy Reporting Requirements 
 
The Principal Investigator must be notified within 24 hours of any 
pregnancies occurring in a female patient or a female partner of a male 
patient along with pregnancy outcomes. Elective abortions without 
complications should not be considered adverse events unless they were 
therapeutic abortions. Hospitalization for normal delivery of a healthy 
newborn should not be considered a significant adverse event. 
Spontaneous abortions should always be reported as significant adverse events. 
 
The Investigator should follow-up with the study patient or the female partner of the study 
patient until delivery or termination of pregnancy, even if the patient was withdrawn from the 
clinical study or the clinical study was completed. Depomed will be informed of all pregnancy 
outcomes using the contact information provided above. 
8.0 
AGENT INFORMATION 
8.1 
Lazanda® 
Please refer to Investigator’s Brochure for more comprehensive information. 
 
Other names for the drug: Fentanyl Nasal Spray CII 
 
Mechanism of action (or Product description): Fentanyl is a pure opioid agonist whose 
principal therapeutic action is analgesia. Pharmacological effects of opioid agonists include 
anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough 
suppression, and analgesia. Its active ingredient, fentanyl citrate, USP is N-(1-phenethyl-4-


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 35 of 53 
Protocol Date 03/19/2018 
piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water 
partition coefficient at pH 7.4 is 816.1). Fentanyl citrate is sparingly soluable in water (1:40). The 
molecular weight of the free base and citrate salt are 336.5 and 528.6, respectively. The pKa is 
8.4.  
 
Lazanda nasal spray is a liquid formulation of fentanyl citrate intended for intranasal 
transmucosal administration. The product consists of a practically clear to clear, colorless, 
aqeous solution of fentanyl citrate in a glass multidose container to which is attached a metered-
dose nasal spray pump with a visual and audible spray counter. 
 
Availability: provided by Depomed, free of charge 
 
How supplied: Lazanda is supplied in glass bottles, containing 8 sprays of 100 mcL containing 
100 mcg/100 mcL or 400 mcg/100 mcL concentration solution. Each bottle is supplied in a child-
resistant container. Bottles in their child-resistant containers are supplied in cartons containing 1 
to 4 bottles. Each carton contains one carbon-lined pouch per bottle for disposal of priming 
sprays.   
 
 
Lazanda contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an 
abuse liability similar to other opioid analgesics. Lazanda® can be abused in a manner similar to 
other opioid agonists, legal or illicit. Because of the risk for misuse, abuse, addiction, and 
overdose, Lazanda® is available only through a restricted program required by the Food and 
Drug Administration, called a Risk Evaluation and Management Strategy (REMS). Under the 
Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, 
healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll 
in this program (see www.TIRFREMSaccess.com). Dr. Roeland, Dr. Ma, and Arlene Cramer, 
NP, have all completed their TIRF REMS education and the Moores Cancer Center provides 
REMS medications.  
 
Prior to initial dosing of Lazanda, subjects will be instructed on the proper use of the study drug 
product, according to the instructions in Section 4.2. Study subjects will receive an initial supply 
of Lazanda, 1 bottle of 100 mcg spray, at the time of radiation therapy simulation for use during 
initial dose titration. A single bottle of Lazanda with increments of 100 mcg sprays will provide 8 
doses. Subjects will receive additional supply of Lazanda bottles, 5 mL bottles of 100 mcg or 
400 mcg or combination of both, at the first radiation treatment visit as determined by the 
investigator based on opioid needs and the dose established during titration procedures. If the 
response to the titrated Lazanda dose markedly changes, an adjustment of dose may be 
necessary to ensure that an appropriate dose is maintained, and may require a refill supply 
during the course of radiation treatment as determined by dose adjustment and in discussion 
with the Principal Investigator. All doses will be carefully monitored and recorded and 
participants will not receive surplus bottles.  
 
Storage and stability: Lazanda will be stored at up to 25C in the Moores Cancer Center 
Investigational Drug Services (IDS). Do not freeze. Bottles for individual patient use will be 
returned to the child-resistant container and in the carbon-lined pouch in the cardboard carton 
for secure storage at home after each use. Lazanda must be stored out of reach of children and 
protected from light.  
 
Preparation: Bottles containing Lazanda will be supplied in ready-to-use form. No further drug 
preparation (e.g., reconstitution, dilution) is required by IDS prior to labeling and dispensing. 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 36 of 53 
Protocol Date 03/19/2018 
Route of administration for this study: Lazanda will be administered as an intranasal spray. 
Each actuation on the metered-dose nasal spray counter is designed to deliver a spray of 100 
mcL of solution containing 100 mcg or 400 mcg fentanyl base. This enables doses of 100 mcg 
or 400 mcg to be administered using a single spray into one nostril (100 mcg), a single spray 
into each nostril (200 mcg), or two sprays into each nostril (400 mcg), based on the effective 
and tolerable dose determined through titration steps described in Section 4.2.  
 
Side effects: The most commonly observed adverse events (frequency >5%) seen with 
Lazanda are typical of opioid side effects, such as nausea, vomiting, constipation, dizziness, 
pyrexia, somnolence and headache. Please refer to the Lazanda Package Insert for additional 
detail on adverse events experienced less commonly (frequency >1%). 
 
8.1.1 Return and Retention of Study Drug 
Patients will return remaining study drug supply to a member of the study team who will log the 
return with IDS. Remaining drug is to be destroyed on-site, according to UCSD Moores Cancer 
Center IDS drug destruction policy.  
8.1.2 Drug Accountability/Subject Compliance 
Records of study medications used, dosages administered, and intervals between visits will be 
kept during the study. Subjects will be asked to fill out a daily study drug diary while taking 
Lazanda and bring with them, along with any unused study drug, on each visit to clinic for review 
with a member of the study team. 
 
Final drug accountability will be noted at the completion of the trial. Patients will be asked to 
return all unused medication at the end of the study. 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
This is an open label, single center, phase II case study. The primary endpoint is PID15, the 
difference in pain intensity as measured by the NRS-11 between the time of laying down on the 
hard surface (0 minutes) and the pain intensity at 15 minutes after laying down on the hard 
surface. Secondary endpoints include change in bone pain severity scores as measured on the 
BPI-sf, and the rate of drug-related adverse events experienced assessed according to the 
NCI’s CTCAE v4.03 toxicity criteria. Exploratory endpoints will include total recumbent time at 
each fractionation visit measured in minutes, as well as baseline pain intensity score and 24-
hour opioid use (oral morphine equivalents). 
9.2 
Sample Size and Accrual 
This trial will enroll approximately 6 subjects meeting the eligibility criteria described above. 
Conservatively assuming a 10% drop out rate, we will accrue  5 patients. Many of the study 
variables are observational and descriptive. These are best analyzed as they relate to the 
individual participant experience.   
 
Sample size was calculated PASS (NCSS, LLC. Kaysville, Utah).  
 
There is limited literature relating to the change in pain intensity-NRS pain scores in cancer 
patients. Previous literature has reported the interquartile range (IQR) for the change in pain 
intensity-NRS pain score across various patient categories. These IQRs ranged between 1 and 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 37 of 53 
Protocol Date 03/19/2018 
3, thus we used and an estimated IQR of 2 to get a standard deviation of 1.48 (by assuming a 
normal distribution for differences in pain scores)2.  
Accrual Targets 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
6 
7 
13 
Ethnic Category: Total of all subjects 
7 
8 
15 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
5 
6 
11 
Racial Category: Total of all subjects 
7 
8 
15 
9.3 
Data Analyses Plans 
All analyses will be conducted using SAS version 9.4 (Cary, NC, USA). 
 
9.3.1 Primary Analysis 
Our primary aim of assessing the change in NRS-11 scores of patients before and after 
receiving Lazanda will be analyzed using a linear mixed-effects model to account for the 
repeated daily dosing. We will model the difference in PID from baseline to 15 minutes (PID15) 
at each radiation simulation and fractionation visit; with a fixed intercept term for time and a 
subject level random  intercept to account for within-patient variability. We will provide 
descriptive statistics overall and for each treatment day (day 1, …, n). Descriptive statistics will 
include mean/standard deviation, min, max and IQR.  
 
 
9.3.2 Safety Endpoint 
Safety endpoints will be evaluated by monitoring AEs from clinical and laboratory reporting. 
Adverse events will be classified according to the NCI-CTCAE version 4.03. Trends in the 
distribution and severity of the AEs across the study groups will be assessed by examining the 
count of total AEs and count of AEs at each severity level over the course of the subject’s 
participation in the study. 
 
9.3.3 Secondary Analyses 
To analyze patient reported pain severity using the BPI-sf, we will calculate the "worst pain" i.e., 
the arithmetic mean of the four severity items to measure pain severity. We will model the 
difference in "worst pain” from baseline to 15 minutes at each radiation simulation and 
fractionation visit; with a fixed intercept term for time and a subject level random intercept to 
account for within-patient variability. We will provide descriptive statistics overall and for each 
treatment day ( mean/standard deviation and frequency distributions of “worst pain”).  
 
9.3.4 Exploratory Analyses 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 38 of 53 
Protocol Date 03/19/2018 
Our exploratory aim will assess the impact of Lazanda on treatment delivery efficiency. This will 
be assessed by comparing treatment delivery efficiency in the Lazanda treated patients to the 
historic average. To assess this we will quantify each subjects average total time on the 
treatment table (averaged across each subjects fractionation visits, in minutes). This average 
will be compared to the clinic’s historic average of 6 minutes using a one-sample t-test of the 
null hypothesis that the average time on the treatment table for Lazanda study patients equals 6 
minutes. 
 
We will also consider the effects of baseline pain intensity score, 24-hour opioid use (oral 
morphine equivalents) and total treatment time at each fraction (minutes) on the change in pain 
intensity by including each of them as fixed effects in the linear mixed-effects models for PID15. 
The use of continuous assessment for each individual participant strengthens the validity of the 
research.20  Our final case series report will assess the overall effect of the study drug on the 
participant radiotherapy related pain as determined by NRS-11 scores, BPI-sf results, and AEs. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities. It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
10.3 
Registration Procedures  
All patients must be registered with the UCSD Moores Cancer Center Clinical Trials Office 
before enrollment to study. Prior to registration, eligibility criteria must be confirmed and an 
eligibility checklist completed. Once eligibility is confirmed, patient will be given a unique 
sequential study number. 
10.4 
Data Collection and Management 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 39 of 53 
Protocol Date 03/19/2018 
Records and data to be obtained from the study subjects are detailed above in the Schedule of 
Events. Subject outcome information will be documented in the electronic medical record and 
subject’s research record. Data for this study will be entered into a password-protected set of 
electronic case report forms via the Velos eResearch web-based system. Velos eResearch is 
an integrated software system for managing clinical trials. This system supports several clinical 
trial functions, including electronic case report forms, tracking and scheduling of subject visits 
and events, and study reporting. The software links to the UCSD Health System’s Epic 
Electronic Medical Record System to provide improved information and integration for clinical 
research projects. A robust support team assists investigators in implementing protocols and 
calendars and building electronic case report forms. Velos provides automated data export 
procedures for designated users into Excel, and then transferred into SAS and R. Access to the 
Velos database for this study will be limited to those users required to perform study-specific 
functions such as data entry and monitoring. A designated study coordinator from the UCSD 
Moores Cancer Center Clinical Trials Office will be responsible for entering all study data. 
10.5 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
10.6 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the principal investigator and 
co-investigators, quality assurance of the study will be performed by a UCSD Moores Cancer 
Center Clinical Trials Office internal monitor. Monitoring intervals will be dependent upon the 
rate of enrollment, and are anticipated to occur approximately every 3-4 months.  
 
This study will also use the UCSD Moores Cancer Center DSMB to provide oversight in the 
event that this treatment approach leads to unforeseen toxicities. Data from this study will be 
reported every 6 months and will include 
1) the protocol title, IRB protocol number, and the activation date of the study.  
2) the number of patients enrolled to date  
3) the dates of patient enrollment 
4) a summary of all adverse events regardless of grade and attribution  
5) outcome data for evaluable patients when available 
6) a summary of any recent literature that may affect the ethics of the study.  
 
It will be left to the Investigator’s clinical judgment whether or not an adverse event is related 
and of sufficient severity to require the subject’s removal from treatment. Subsequent review of 
serious, unexpected and related adverse events by the principal investigator, DSMB, UCSD 
and/or HRPP, may also result in suspension of further trial interventions/ administration of study 
drug at a site. The principal investigator retains the authority to suspend additional enrollment 
for the entire study as applicable. 
10.7 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators are required to conduct their 
research according to the plans reviewed and approved by the IRB.  
10.8 
Emergency Modifications 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 40 of 53 
Protocol Date 03/19/2018 
Investigators may implement a deviation from, or a change of, the protocol to eliminate apparent 
immediate hazards/risks to trial subjects without prior IRB approval. Any such emergency 
modification implemented must be noted and reported to the IRB along the lines of a protocol 
deviation or violation, depending on the nature of the modification.  
10.9 
Protocol Violations 
Any unplanned variance from an IRB approved protocol is considered a violation and must be 
reported to the IRB in a timely fashion. 
 
A) Major violations must be reported to the IRB within 10 working days of awareness of 
the violation. Major violations include: 
• 
Instances that have harmed or increased the risk of harm to one or more 
research participants. 
• 
Instances that have damaged the scientific integrity of the data collected for the 
study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
B) Minor violations may be reported to the IRB at the time of the continuing review. 
Minor violations have no substantive effect on the risks to participants or on the 
scientific integrity of the research plan or the value of the data collected. 
10.10 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment to 
the protocol substantially alters the study design or the potential risk to the patient, a revised 
consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the UCSD 
IRB for approval prior to implementation. 
10.11 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
10.12 Obligations of Investigators 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 41 of 53 
Protocol Date 03/19/2018 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. At the completion of the study, all 
case report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
 
10.13 Data Reporting 
 
The study findings will be disseminated as a prospective case series wherein related participant 
medical history will be reported. The degree and length of the medical history reporting will vary 
by participant. At the PI’s discretion, only events and factors significant to the present study that 
are fully de-identified will be included in the dissemination of findings. Historic factors related to 
individual participant pain will be considered and can include past pain medication and radiation 
experience, or any diagnosis that contributes to radiation therapy pain.  
 
 
 
11.0 
REFERENCES 
 
1. Jackson D. Brief Pain Inventory-Short Form. 
2. Portenoy RK. Appropriate use of opioids for persistent non-cancer pain. Lancet. 
2004;364(9436):739-740. 
3. Davies A, Zeppetella G, Andersen S, et al. Multi-centre European study of breakthrough 
cancer pain: pain characteristics and patient perceptions of current and potential 
management strategies. European journal of pain (London, England). 2011;15(7):756-
763. 
4. Simon SM, Schwartzberg LS. A review of rapid-onset opioids for breakthrough pain in 
patients with cancer. Journal of opioid management. 2014;10(3):207-215. 
5. Schrijvers D. Pain control in cancer: recent findings and trends. Annals of oncology : 
official journal of the European Society for Medical Oncology / ESMO. 2007;18 Suppl 
9:ix37-42. 
6. Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the 
WHO method for cancer pain relief. Cancer. 1987;59(4):850-856. 
7. Mercadante S. Pharmacotherapy for breakthrough cancer pain. Drugs. 2012;72(2):181-
190. 
8. Fisher A, Watling M, Smith A, Knight A. Pharmacokinetic comparisons of three nasal 
fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188. Int J Clin Pharmacol 
Ther. 2010;48(2):138-145. 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 42 of 53 
Protocol Date 03/19/2018 
9. Perelman M, Fisher AN, Smith A, Knight A. Impact of allergic rhinitis and its treatment on 
the pharmacokinetics of nasally administered fentanyl. Int J Clin Pharmacol Ther. 
2013;51(5):349-356. 
10. Perelman M, Knight A. A pharmacokinetic assessment of an alternate titration strategy 
for fentanyl pectin nasal spray. Int J Clin Pharmacol Ther. 2013;51(12):942-947. 
11. Portenoy RK, Burton AW, Gabrail N, Taylor D. A multicenter, placebo-controlled, double-
blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment 
of breakthrough cancer pain. Pain. 2010;151(3):617-624. 
12. Taylor D, Galan V, Weinstein SM, Reyes E, Pupo-Araya AR, Rauck R. Fentanyl pectin 
nasal spray in breakthrough cancer pain. J Support Oncol. 2010;8(4):184-190. 
13. Davies A, Sitte T, Elsner F, et al. Consistency of efficacy, patient acceptability, and nasal 
tolerability of fentanyl pectin nasal spray compared with immediate-release morphine 
sulfate in breakthrough cancer pain. Journal of pain and symptom management. 
2011;41(2):358-366. 
14. Fallon M, Reale C, Davies A, et al. Efficacy and safety of fentanyl pectin nasal spray 
compared with immediate-release morphine sulfate tablets in the treatment of 
breakthrough cancer pain: a multicenter, randomized, controlled, double-blind, double-
dummy multiple-crossover study. J Support Oncol. 2011;9(6):224-231. 
15. Mercadante S, Prestia G, Adile C, Casuccio A. Intranasal fentanyl versus fentanyl pectin 
nasal spray for the management of breakthrough cancer pain in doses proportional to 
basal opioid regimen. J Pain. 2014;15(6):602-607. 
16. Portenoy RK, Raffaeli W, Torres LM, et al. Long-term safety, tolerability, and consistency 
of effect of fentanyl pectin nasal spray for breakthrough cancer pain in opioid-tolerant 
patients. Journal of opioid management. 2010;6(5):319-328. 
17. Cleeland C, Ryan K. Pain assessment: global use of the Brief Pain Inventory. Annals of 
the Academy of Medicine, Singapore. 1994;23(2):129-138. 
18. Ma JD, Horton JM, Hwang M, Atayee RS, Roeland EJ. A Single-Center, Retrospective 
Analysis Evaluating the Utilization of the Opioid Risk Tool in Opioid-Treated Cancer 
Patients. Journal of Pain and Palliative Care Pharmacotherapy. 2014;28(1):4-9. 
19. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing Numerical Rating 
Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain 
intensity in adults: a systematic literature review. J. Pain Symptom Manage. 
2011;41(6):1073-1093. 
20. Kazdin, A. E. (1981). Drawing valid inferences from case studies. Journal of Consulting 
and Clinical Psychology, 49(2), 183-192. http://dx.doi.org/10.1037/0022-006X.49.2.183 
Retrieved from https://search.proquest.com/docview/614330467?accountid=14524 
 
 
12.0 
APPENDICES 
 
Appendix A: ECOG Performance Status Scale 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 43 of 53 
Protocol Date 03/19/2018 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair 
5 
Dead. 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 44 of 53 
Protocol Date 03/19/2018 
Appendix B. Strong and Moderate CYP3A4 Inhibitors 
 
Strong CYP3A4 inhibitors allowed during study and include but are not limited to the following: 
• 
Boceprevir 
• 
Clarithromycin 
• 
Conivaptan 
• 
Grapefruit juice 
• 
Indinavir 
• 
Itraconazole  
• 
Ketoconazole  
• 
Lopinavir/ritonavir 
• 
Mibefradil 
• 
Nefazodone  
• 
Nelfinavir 
• 
Posaconazole  
• 
Ritonavir, 
• 
Saquinavir  
• 
Telaprevir 
• 
Telithromycin 
• 
Voriconazole 
 
Moderate CYP3A4 inhibitors are allowed during study and include but are not limited to the 
following: 
• 
Amprenavir 
• 
Aprepitant, 
• 
Atazanavir,  
• 
Ciprofloxacin, 
• 
Darunavir/ritonavir,  
• 
Diltiazem,  
• 
Erythromycin,  
• 
Fluconazole,  
• 
Fosamprenavir,  
• 
Grapefruit juice, 
• 
Imatinib,  
• 
Verapamil 
 
 
Please refer to the U.S. Food and Drug Administration website, Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers, for additional information:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 45 of 53 
Protocol Date 03/19/2018 
Appendix C. Numerical Rating Score (NRS) for Pain 
 
 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 46 of 53 
Protocol Date 03/19/2018 
Appendix D. Brief Pain Inventory-short form (BPI-sf) 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 47 of 53 
Protocol Date 03/19/2018 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 48 of 53 
Protocol Date 03/19/2018 
Appendix E. Medication Use Diary 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 49 of 53 
Protocol Date 03/19/2018 
Appendix F. Laxation Diary  
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 50 of 53 
Protocol Date 03/19/2018 
Appendix G. Nausea/Vomiting Diary 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 51 of 53 
Protocol Date 03/19/2018 
Appendix H. Study Drug Diary   
 
 
 
 
 
 
 
 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 52 of 53 
Protocol Date 03/19/2018 
Appendix I. NRS Scale Log 
 


UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Lazanda for Cancer Pain with Palliative Radiation 
 
Protocol Amendment 6 (Version 7.0) 
 
 
 
 
 
Page 53 of 53 
Protocol Date 03/19/2018