Conditions: Neoplasm Skull Base Neoplasm
Keywords: head and neck tumor skull base tumor neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This study allows head and neck cancer surgeons to specifically visualize cancerous cells apart from normal healthy tissue. 5-aminolevulinic acid (5-ALA) is a safe and effective FDA-approved agent successfully used by neurosurgeons for FGS of different brain tumors is given to the patients preoperatively. Using specific wavelengths of light as well as specialized magnified lenses the surgeons use this technique to assist in tumor resection.

Detailed description:
Treatment for many head and neck cancer involves surgical resection, or removal, of the tumor. A potential outcome of surgery is subtotal resection, in which some cancerous material fails to be removed resulting in tumor recurrence and lower overall survival. Achieving total resection without interfering with normal tissue is a challenge due the critical anatomical structures of the head and neck. Fluorescent-guided surgery (FGS) is a new method of intraoperative imaging that can be used to clearly visualize cancerous tissue aprt from normal tissue during surgery in real-time. Before surgery, an agent that preferentially enters tumor cells is given to the patient. Tumor cells then glow brightly when exposed to specific wavelengths of light during surgery, allowing the surgeon to easily distinguish between healthy and cancerous tissue. 5-aminolevulinic acid (5-ALA) is a safe and effective FDA approved agent successfully used by neurosurgeons for FGS of different brain tumors which has not been assessed for use in head and neck cancers. The aim of the study is to determine if 5-ALA can be effectively used in FGS for different types of head and neck cancers, and if it will improve survival, tumor regrowth, and other outcomes for patients. 23 patients will be enrolled from the Mount Sinai Hospital, New York Eye and Ear Infirmary and Mount Sinai Union Square Faculty Practices over a 1 year period and will be completed by December 2022.

Arms:
arm 1: Gleolan® is available in colorless glass vials containing 1.5 g 5-aminolevulinic acid hydrochloride (Gleolan®) Gleolan® is administered orally to patients prior to tumor removal by surgery (20 mg/kg BW).

Interventions: intervention 1: 5-Aminolevulinic acid Hydrochloride
Intervention descriptions: intervention 1: The closure consists of colorless glass vial (Type II, Ph Eur) and bromobutyl-rubber stopper ø 20 mm (Type I, Ph Eur) and flip cap. The powder for oral solution is intended for single (partial) use. To prepare the ready-to-use solution the content of one vial is dissolved in 50 ml of water or apple juice. The concentration of the reconstituted solution is 3%. Gleolan® is administered orally to patients prior to tumor removal by surgery (20 mg/kg BW). The reconstituted solution may be prepared up to 24 hours prior to use if protected from light. It should be given 3 hours (range 3-5 hours) prior to planned induction of anesthesia for surgery, although its effect is present for up to 8-12 hours. This step is critical for an optimal visualization of tumor tissue due to pharmacokinetic properties of Gleolan®.

Protocol document:
Prot_SAP_000.pdf: 
The Role of 5-Aminolevulinic Acid Fluorescence-Guided Surgery in Head and
Neck Cancers: a Pilot Trial
PI: Alfred-Marc Iloreta, MD
NCT05101798
Document Date: 12-20-2024


The Role of 5-Aminolevulinic Acid Fluorescence-Guided Surgery in Head and Neck Cancers: a 
Pilot Trial
Principal Investigator:
Alfred-Marc Iloreta, MD
Mount Sinai 
1 Gustave L Levy Place
10th Floor
New York, New York 10020
Office: 212-241-9410 
Email: Alfred-Marc.Iloreta@mountsinai.org
Sub-Investigator(s):
Joshua Bederson, MD
Department of Neurosurgery
Raj Shrivastava, MD
Department of Neurosurgery
Eric Genden, MD
Department of Otolaryngology
Satish Govindaraj, MD
Department of Otolaryngology
Marita Teng, MD
Department of Otolaryngology
Mohemmed Khan, MD
Department of Otolaryngology
Scott Roof, MD
Department of Otolarygology
Peter Filip
Department of Otolaryngology
David Lerner
Department of Otolaryngology
Evan Kominsky
Department of Otolaryngology
Biostatistician:
Hsin-Hui Huang, MD, PhD, MS, MPH
Biostatistician 
Mount Sinai Health System 
Department of Population Health Science and Policy
1425 Madison Avenue, New York, NY 10029
Phone: 212-659-5520 
E-mail: hsin-hui.huang@mountsinai.org
Study Drug:
5-Aminolevulinic Acid, Gleolan®
Effective Date: 12/20/2024
End Date:12/19/2025


Funding Source: 
Mount Sinai Rhinology Department
Revision History:
Version
Number
Date
Summary of Revisions Made:
0.0
11/12/2018
Initial version
1.0
11/19/2019
BDW Approved
2.0
8/20/2021
Modified Co-Investigators 
Updated Data Safety Monitoring Team
3.0
9.7.2021
Data retention period modified
4.0
12.13.2023
Extend study completion date 
Expand the protocol to include all upper aerodigestive head and 
neck cancers in addition to squamous cell carcinoma
Effective Date: 12/20/2024
End Date:12/19/2025


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.
Principal Invesigator (PI) Name: 
Alfred-Marc Iloreta, MD
PI Signature: 
 Alfred-Marc Iloreta
Date: 
Effective Date: 12/20/2024
End Date:12/19/2025


STUDY-20-00713
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i
TABLE OF CONTENTSRevision History:.....................................................................................ii
LIST OF ABBREVIATIONS............................................................................................1
STUDY SCHEMA .............................................................................................................2
STUDY SUMMARY ..........................................................................................................2
1.0............................................................................BACKGROUND AND RATIONALE
..............................................................................................................................................4
1.1
Background .....................................................................................................................4
1.2
Study Agent(s) Background and Associated Known Toxicities.......................................4
2.0....................................................................................................STUDY OBJECTIVES
..............................................................................................................................................7
2.1
Primary Objectives ..........................................................................................................8
2.2
Secondary Objectives......................................................................................................8
2.3
Endpoints.........................................................................................................................8
3.0...................................................................................................PATIENT ELIGIBILITY
..............................................................................................................................................8
3.1
Inclusion Criteria..............................................................................................................9
3.2
Exclusion Criteria.............................................................................................................9
4.0 .......................................................................................................TREATMENT PLAN
............................................................................................................................................10
4.1
Treatment Dosage and Administration..........................................................................10
4.2
Toxicities and Dosing Delays/Dose Modifications.........................................................11
4.3
Concomitant Medications/Treatments...........................................................................11
4.4
Other Modalities or Procedures.....................................................................................11
4.5
Duration of Therapy.......................................................................................................12
4.6
Duration of Follow Up....................................................................................................12
4.7
Removal of Patients from Protocol Therapy..................................................................13
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STUDY-20-00713
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4.8
Patient Replacement .....................................................................................................13
5.0 .................................................................................................STUDY PROCEDURES
............................................................................................................................................13
5.1
Screening/Baseline Procedures (60-0 days before surgery).........................................13
5.2
Procedures During Treatment .......................................................................................14
5.3
Follow-up Procedures....................................................................................................14
5.4
Time and Events Table..................................................................................................15
5.5
Removal of Subjects from Study ...................................................................................15
6...........................................................................................................ADVERSE EVENTS
............................................................................................................................................16
6.1
Adverse Event Monitoring .............................................................................................16
6.2
Definitions......................................................................................................................16
6.3
Steps to Determine If an Adverse Event Requires Expedited Reporting ......................18
6.4
Reporting Requirements for Adverse Events ................................................................18
6.5
Stopping Rules ..............................................................................................................19
7.0...................................................................................................DRUG INFORMATION
............................................................................................................................................20
7.1    Gleolan® ...........................................................................................................................20
8.0 ............................................................................STATISTICAL CONSIDERATIONS
............................................................................................................................................21
8.1
Study Design/Study Endpoints......................................................................................21
8.2
Sample Size and Accrual ..............................................................................................21
8.3
Data Analyses Plans .....................................................................................................22
9.0 ................................................................................................STUDY MANAGEMENT
............................................................................................................................................23
9.1
Conflict of Interest..........................................................................................................24
9.2
Institutional Review Board (IRB) Approval and Consent...............................................24
9.3
Required Documentation...............................................................................................24
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9.4
Registration Procedures................................................................................................24
9.5
Data Management and Monitoring/Auditing ..................................................................25
9.6
Adherence to the Protocol.............................................................................................26
9.7
Amendments to the Protocol .........................................................................................27
9.8
Record Retention...........................................................................................................27
9.9
Obligations of Investigators ...........................................................................................27
10.0...............................................................................................................REFERENCES
............................................................................................................................................28
11.0................................................................................................................APPENDICES
............................................................................................................................................31
Effective Date: 12/20/2024
End Date:12/19/2025


STUDY-20-00713
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1
LIST OF ABBREVIATIONS
5-ALA
5-Aminolevulinic Acid
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
FGS
Fluorescence-Guided Surgery
H&P
History & Physical Exam
HRPP
Human Research Protections Program
IV (or iv)
Intravenously
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate
OS
Overall Survival
p.o.
per os/by mouth/orally
PPV
Positive Predictive Value
PR
Partial Response
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
Effective Date: 12/20/2024
End Date:12/19/2025


STUDY-20-00713
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STUDY SCHEMA
STUDY SUMMARY
Title
The Role of 5-Aminolevulinic Acid Fluorescence-Guided Surgery in 
Head and Neck Cancers: a Pilot Trial
Short Title
5-ALA FGS Pilot Trial for Head and Neck Cancer
Protocol Number
The standard protocol number used to identify this study- N/A
Methodology
Open label single institution pilot study
Study Duration
21/2 years
Study Center(s)
Single center
Objectives
The objectives of this study are to determine the feasibility of using 5-
ALA in fluorescence-guided surgery of head and neck and skull base 
malignancies.
Number of Subjects
23
Diagnosis and Main 
Inclusion Criteria

Resectable head and neck or skull base malignancy

Age 18-80

Karnofsky score >60%, adequate marrow and organ function

Not pregnant

Able to give consent
Study Product(s), Dose, 
Route, Regimen
Single dose administration of oral Gleolan® (5-ALA) (20mg/kg) 3-5h prior 
to surgery
Duration of administration
Day of surgery
Reference therapy
N/A
Statistical Methodology
     Assuming a prevalence of 75% and a sample sensitivity of 85%, the 
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STUDY-20-00713
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3
sample size needed to estimate a two-sided 95% sensitivity confidence 
interval with a width of at most 35% (± 17.5% precision assuming 
asymptotic with continuity correction method) is at least 23). The sample 
size calculation is performed conservatively assuming only 1 measure per 
patient, but there will be typically 4 per patient which will improve 
precision of estimates. 
We expect to enroll the necessary patients in 6 months at a rate of 
approximately 4 patients per month. This accrual rate is based on 
historical monthly rates of surgery in this patient population at the Mount 
Sinai hospital. 
Analysis of the primary endpoint
      To assess the performance of 5-ALA as a feasible method to detect 
tumor tissues, the point estimate of sensitivity will be computed according 
to the following definition:
Sensitivity: proportion of tumor tissues that tested positive on 5-ALA 
induced fluorescence.
        The definition of a positive test is the fluorescence score equal to or 
greater than 1. For the assessment of sensitivity and specificity, 
histological diagnoses of any upper aerodigestive head and neck cancer 
in addition to squamous cell carcinoma, carcinoma in situ, and severe 
and moderate dysplasia were classified as malignant, whereas light 
dysplasia and normal tissue will be classified as benign by pathologists. 
Each patient is expected to contribute multiple samples and the 
pathologists will determine presence of malignancy in each sample. A 
contiguous table (fluorescence scores vs. pathological results) that 
presents the frequency and percentage of each cell will be prepared. A 
generalized estimating equation (GEE) model accounting for repeated 
measure within each patient will be used to estimate the sensitivity, 
specificity, PPV, and NPV. For sensitivity and specificity, the dependent 
variable is the PPIX fluorescence test result (positive vs. negative) and 
the independent variable is presence of tumor cells (tumor vs. normal). 
Analysis of the secondary endpoints
      For specificity, the point estimate will be computed according to the 
following definition:
Specificity: proportion of normal tissues that tested negative on 5-ALA 
induced fluorescence.
      The definition of a negative test is a fluorescence score of 0. For 
sensitivity and specificity, the dependent variable is the PPIX 
fluorescence test result (positive vs. negative) and the independent 
variable is presence of tumor cells (tumor vs. normal).
  For PPV and NPV, the dependent variable is presence of tumor and the 
independent variable is the test result. The point estimate along with a 
corresponding two-sided 95% confidence interval will be provided using 
PROC GENMOD.    
        The 5-ALA related adverse events will be recorded using 
standardized toxicity criteria and known side effect profile. Frequency of 
each observed adverse event will be calculated at each monitor time 
point. The rate of each adverse effect will be estimated as the number of 
adverse events within 6 weeks after surgery divided by the number of 
person days followed. The point estimate of the incidence rate along with 
a corresponding two-sided 95% confidence interval will be provided using 
PROC GENMOD. A generalized estimating equation (GEE) model 
accounting for repeated measure within each patient will be used to 
estimate the sensitivity, specificity, PPV, and NPV. 
Effective Date: 12/20/2024
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STUDY-20-00713
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4
1.0
BACKGROUND AND RATIONALE
1.1
Background
5-ALA has been used in the treatment of malignant gliomas in neurosurgical interventions. FGS
permits the intraoperative visualization of malignant tissue in real time guidance for differentiating
tumor from normal brain tissue that is independent of neuronavigation. Tissue fluorescence after
oral administration of 5-ALA has high sensitivity, specificity, and positive predictive values for
identifying malignant glioma tumor tissue. 5-ALA-induced tumor fluorescence in diffusely
infiltrating gliomas with non-significant magnetic resonance imaging contrast-enhancement
permits intraoperative identification of anaplastic foci and establishment of an accurate
histopathological diagnosis for proper adjuvant treatment. We conducted an extensive literature
review and noted no current applications to sinonasal skull base tumors or head and neck
tumors.
5-ALA is a hemoglobin metabolic pathway metabolite that can be orally administered. It
accumulates within tumor tissue and surrounding infiltrative cancer cells and is metabolized into
protoporphyrin IX (PpIX), a fluorescent metabolite that that can be visualized after activation with
405nm blue light. As factors associated with 5-ALA fluorescence include cellular density, tumor
cell proliferative activity, and neovascularization, elevated PpIX production and tissue
fluorescence is a highly sensitive, specific, and positive predictor marker for malignant tumor
tissue.3 While other fluorescent markers such as fluorescein sodium have been demonstrated to
be efficacious for FGS as well, one study found 5-ALA to be better for detecting tumor cells,4 and
another found it more cost-effective.5 Therefore 5-ALA was chosen as the target of this
investigation.
The utility of intraoperative 5-ALA has been demonstrated through its development for 
neurosurgical resection of glioma,5-14 glioblastoma multiforme,15,16 medulloblastoma,17 
meningioma and other intracranial tumors,12 as well as spinal tumors.18 It has been shown to be 
safe for intraoperative use,19 to increase gross total resection rates,5 and to yield high positive 
predictive value for tumor tissue.20 Similarly, 5-ALA has been shown to be more sensitive than 
contrast MRI or PET scan in glioblastoma resection,20,21 and to yield a synergistic effect in 
improving glioma resection outcomes when combined with intraoperative MRI.22
In recent years, many surgical subspecialties have increasingly recognized the utility of 5-ALA at 
accurately visualizing precancerous and cancerous tissue. Its use has expanded to photodynamic 
diagnosis and phototherapy of urothelial,23 gastric,24 prostate,25 and ovarian cancers.26 In 
particular, 5-ALA has also shown utility in identifying oral cancers,27 and in endoscopic 
identification of laryngeal malignancies in conjunction with autofluorescence bronchoscopy.28-32 
Similarly, trials with autofluorescence have successfully demonstrated the effectiveness of 
fluorescence-based technologies at improving head and neck cancer detection and increasing 
successful surgical margins of oral squamous cell carcinoma excision.33,34 While 5-ALA FGS and 
other fluorescence-based techniques appear promising for potential use in head and neck 
malignancies,35 no clinical trials have yet assessed intraoperative use of 5-ALA for improving 
resection of head and neck cancers and skull base tumors.
1.2
Study Agent(s) Background and Associated Known Toxicities
1.2 5-Aminolevulinic Acid 
5-ALA is a naturally occurring substance that is found in all organisms, including humans, and is
a necessary part of many basic metabolic life processes.
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End Date:12/19/2025


STUDY-20-00713
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5
5-Aminolevulinic Acid HCl 
C5H9NO3 MW 167.6 
Approximately 350 mg of 5-ALA is synthesized in humans each day for heme production. 
Administration of exogenous 5-ALA, results in the production of high intracellular (mitochondrial) 
concentrations of (PPIX). 5-ALA and PPIX (and other porphyrins) are respectively excreted in the 
urine and the stool. 
1.2.1 Pharmacology 
Aminolevulinic acid (ALA) is the first step in the biochemical synthesis of hemoglobin in animals. 
Aminolevulinic acid is a metabolic precursor of protoporphyrin IX (PPIX), which is a 
photosensitizer. The metabolism of 5-ALA is normally tightly controlled by feedback inhibition 
reflecting likely the intracellular levels of hemoglobin. The feedback control is through the 
enzyme, 5-ALA synthetase. Exogenous oral 5-ALA, bypasses this feedback inhibition and PPIX 
accumulates to be converted into heme. Excess 5-ALA and PPIX are thus excreted. 
1.2.2 Pharmacokinetics 
General characteristics 
5-ALA is soluble in water and well absorbed through the GI tract. After ingestion, 5-ALA dosing at 
20mg/kg, is metabolized to fluorescent porphyrins, predominantly protoporphyrin IX (PPIX). 
Absorption 
5-ALA HCl as an oral solution is rapidly and completely absorbed and peak plasma levels of 5- 
ALA are reached 0.5-2 hours after oral administration of 20 mg/kg body weight. With a terminal 
half-life of 45 minutes, plasma levels return to baseline values 24 hours after administration of an 
oral dose of 20 mg/kg/ body weight. 5-ALA is generally given on an empty stomach prior to 
induction of anesthesia. 
Distribution and Biotransformation 
Oral 5-ALA is metabolized by the liver, kidney, endothelial cells, skin, as well as by malignant 
gliomas (WHO grade III and IV) and metabolized to fluorescent PPIX. The plasma protein binding 
of 5-ALA is 12%. Four hours after oral administration of 20 mg/kg/body weight 5-ALA HCl, the 
maximum PPIX plasma level is reached. PPIX plasma levels rapidly decline and are not 
detectable 48 hours after administration. In a human pharmacokinetic study (N= 6) using a 128 
mg dose of sterile intravenous 5-ALA HCl and oral 5-ALA HCl (equivalent to 100 mg 5-ALA) in 
which plasma 5-ALA and PPIX were measured, the mean half-life of 5-ALA was 0.70 ± 0.18 h 
after the oral dose and 0.83 ± 0.05 h after the intravenous dose. The oral bioavailability of 5- ALA 
was 50-60% with a mean Cmax of 4.65 ± 0.94 μg/mL. PPIX concentrations were low and were 
detectable only in 42% of the plasma samples. PPIX concentrations in plasma were quite low 
relative to 5-ALA plasma concentrations, and were below the level of detection (10 ng/mL) after 
10 to 12 hours. 
At the oral 5-ALA dose of 20 mg/kg/body weight, tumor:normal brain fluorescence ratios are 
usually high and provide for ‘blue light’ visualization of fluorescent tumor tissue as red-violet for at 
least 9 hours. Besides tumor tissue, faint fluorescence of the choroid plexus has been reported. 
5-ALA is also taken up and metabolized to PPIX by other tissues, e.g. liver, kidneys or skin (see 
section 4.4). 
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STUDY-20-00713
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6
Elimination 
5-ALA is eliminated quickly. Approximately 30% of an orally administered dose of 20 mg/kg/body 
weight is excreted unchanged in urine within 12 hours. 
Linearity/non-linearity 
There is dose proportionality between AUC0-inf. of 5-ALA values and different oral doses of this 
medicinal product. The oral dose (20mg/kg body weight) provides an AUC (mg x h/L) of 26.91 
(mean) and 27.14 (median).
Patients with renal or hepatic impairment
The pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been 
investigated. Renal toxicity of the material has been described in association with acute 
intermittent porphyria and lead exposure.
 
1.2.3 Toxicity 
In vivo toxicological effects associated with elevated levels of 5-ALA, PPIX, and intermediates of 
porphyrin biosynthesis are well known. These characterize metabolic diseases known as 
porphyrias. High systemic concentrations of 5-ALA are associated with neurological abnormalities 
in Acute Intermittent Porphyria (AlP). The relationship is not well understood. 5- ALA and 
Porphobilinogen (PBG = condensation of 2 molecules of 5-ALA) are not neurotoxic when 
administered in large amounts to animals and humans. In porphyric patients, the resulting brain 
or spinal fluid concentration of these precursors is below that required to cause toxicity using in 
vitro models. It is thought that patients with AIP have depletion of hepatic heme and neurologic 
symptoms related to elevated brain concentrations of tryptophan and 5- hydroxytryptamine. Thus 
oral 5-ALA would not deplete hepatic heme, and would not be expected to produce neurological 
symptoms of AlP. Erythropoietic Protoporphyria (EPP) with reduced conversion of PPIX to heme 
is associated with photosensitivity, reflecting high systemic and skin levels of PPIX. Patients with 
EPP experience no hemolytic or neurological problems. 
Side effects of 5-ALA administration are uncommon (>=1/1000, <1/100) and include hypotension, 
nausea, and photosensitivity. Transient nausea and occasional vomiting have been observed 
following oral administration of high doses of 5-ALA. The incidence of nausea 
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STUDY-20-00713
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7
following 30 mg/kg and 60 mg/kg (oral) was 7 and 15%, respectively. No vomiting was observed 
with the lower dose, while 8% of the patients vomited following the higher dose. In all instances, 
the nausea was mild and short lived (less than15 min.). When vomiting occurred, it was mild and 
occurred only once in each patient. The nausea or vomiting occurred within 2.5 to 3 hours after 
receiving the drug which did not interfere with the gut absorption of 5-ALA that occurs within 1 
hour of oral ingestion. 
Abnormalities in liver function have been observed in patients following ingestion of 5-ALA. 
Webber et al. observed that almost one-quarter of all patients who received 5-ALA had at least 
one abnormality in liver function tests. More patients receiving low doses (< 30 mg/kg) developed 
abnormalities than those receiving high doses. Significant variations in the time of appearance of 
the abnormalities were also noted (12 to 120 hr. postoperatively). In all cases, liver function tests 
returned to normal within 2 months after receiving 5-ALA. 
In a single-arm European study including 21 healthy male volunteers, erythema of the skin was 
provoked by direct exposure to ultraviolet light up to 24 hours after oral application of 5-ALA HCl 
(20 mg/kg/ body weight). PPIX photosensitization manifests as an unpleasant pricking, itching, or 
burning sensation under the skin after exposure to the sun. A systemic load above 10 mg/kg is 
required to develop skin photosensitization which lasts from approximately 24 to 48 hours 
following 5-ALA administration. It is for this reason that patients will be kept in subdued light 
conditions for up to 48 hours following surgery. 
Possible drug-related mild nausea was reported in 1 of 21 volunteers. In another single-center 
study, 21 patients with malignant glioma received 0.2, 2, or 20 mg/kg body weight 5-ALA HCl 
followed by fluorescence-guided tumor resection. The only adverse reaction reported in this trial 
was one case of mild skin erythema occurring in a patient treated with the highest dose. 
In a single-arm European study including 36 patients with malignant glioma, drug-related adverse 
events were reported in 4 patients (one patient: mild diarrhea, one patient: moderate hypesthesia, 
one patient: moderate chills, and one patient: arterial hypotension) 30 minutes after dosing with 5- 
ALA HCl20 mg/kg body weight prior to fluorescence-guided resection. Follow-up time was 28 
days. 
In a comparative, unblinded phase-III European trial (MC-ALS.3/GLI), 201 patients with malignant 
gliomas received 5-ALA HCl (20 mg/kg body weight). 176 of these underwent fluorescence-
guided resection with subsequent radiotherapy. 173 patients received standard resection 
(without 5-ALA administration) and subsequent radiotherapy. With a follow-up of at least 180 
days after administration, 2/201 (1.0 %) drug recipients experienced side effects (mild vomiting 48 
hours after surgery and mild photosensitivity 48 hours after study surgery). A patient accidentally 
received an overdose of the medicinal product (3000 mg instead of 1580 mg) which was well 
tolerated. Respiratory insufficiency resolved completely with ventilation. A more pronounced 
asymptomatic transient increase of liver enzymes was observed in 5-ALA HCl recipients, peaking 
between 7 and 14 days. Increased levels of amylase, total bilirubin, and leukocytes, but 
decreased levels of platelets and erythrocytes were observed, but differences between treatment 
groups were not statistically significant. 
Liver toxicity (from phase III European trial) as elevated liver function tests (LFTs) occurred in 
over 10% of patients after oral 5-ALA, anesthesia, and fluorescence-guided tumor resection. LFT 
changes included increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma glutamyltransferase (GGT) and blood amylase at 24 h, 7 d, and 6 weeks after 5- ALA 
ingestion. Approximately, 10% had Grade 3 or 4 elevations in GGT at 7 days; 5% had Grade 3 or 
4 elevations in GGT at 6 weeks, and 1% had persistent ALT or AST at 6 weeks. LFTs returned 
to normal in all patients. In both groups of patients from the European phase III trial, (5-ALA 
and placebo control), 1 patient developed a hepatic serious adverse event (SAE). The 5-ALA 
patient developed cholelithiasis.
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STUDY-20-00713
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8
2.0
STUDY OBJECTIVES
2.1
Primary Objectives
2.1.1
To assess the feasibility of using oral Gleolan® as an adjunct diagnostic imaging 
tool for malignant tumor tissue fluorescence in a pilot cohort of head and neck and skull 
base cancer patients.
2.2
Secondary Objectives 
2.2.1 To further characterize the diagnostic performance of Gleolan ® (5-ALA)-induced 
PPIX tissue fluorescence for detecting malignant tumor histopathology in head and neck 
and skull base cancers.
2.2.2. To determine the predictive values of individual Gleolan® fluorescence scores on 
detecting malignant tumor histopathology in head and neck and skull base 
cancers.
2.3
Endpoints
2.3.1 
Definition:
Safety: Gleolan®-related adverse events will be recorded using standardized toxicity 
criteria and known side effect profile up to 6 weeks after surgery. Monitoring for adverse 
events will take place before and after Gleolan® administration, 48h after surgery, 2 
weeks and 6 weeks postoperatively.
2.3.1
Primary endpoint:
The feasibility of using oral Gleolan® as an adjunct diagnostic imaging tool for malignant 
tumor tissue fluorescence will be primarily assessed by computing sensitivity of 
intraoperative Gleolan® induced PPIX tissue fluorescence.  
PPIX tissue fluorescence will be defined categorically as “no” (score 0), “low” (score 1), 
“medium” (score 2), and “high” (score 3) by operative surgeon, and images will be 
recorded. For purposes of computing measures of diagnostic performance a score of 0 
will be considered a negative test result and a score of 1, 2 or 3 will be considered a 
positive test result.
2.3.2
Secondary endpoints:
2.3.2.1 The diagnostic performance of Gleolan® will further be assessed by computing 
measures of specificity, positive predictive value (PPV), negative predictive value (NPV), 
and accuracy of intraoperative Gleolan® induced fluorescence with a score of 0 will be 
considered a negative test result and a score of 1, 2 or 3 will be considered a positive test 
result.
2.3.2.2 Incidence of Gleolan®-related adverse events
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STUDY-20-00713
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9
3.0
PATIENT ELIGIBILITY
3.1
Inclusion Criteria
3.1.1
Subjects included in this trial must have had documentation of a new or recurrent 
head and neck or skull base tumor for which surgical resection is indicated and 
has been planned. These patients will include those with newly diagnosed or 
recurrent malignancies.
3.1.2
Age 18-80
3.1.3
Karnofsky score >60%
3.1.4
Subjects must have normal organ and marrow function as defined below:
- leukocytes
≥ 3,000/mcL
- absolute neutrophil count
≥ 1,500/mcL
- platelets
≥ 100,000/mcl
- total bilirubin
within normal institutional limits
- AST(SGOT)/ALT(SPGT)
≤ 2.5 X institutional upper limit of normal
- creatinine
within normal institutional limits
OR 
Creatinine clearance >60 mL/min/1.73m2 for patients with creatinine levels above 
institutional normal as defined per institution.
3.1.5
The effects of Gleolan® (5-ALA) on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation. A pregnancy test 
will be performed for all women of childbearing ability prior to surgery (see 
Exclusion Criteria below). Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately.
3.1.6
Ability to understand and the willingness to sign a written informed consent.
3.2
Exclusion Criteria
3.2.1
Patients with non-resectable tumors or not deemed surgical candidates
3.2.2
History of allergic reactions attributed to compounds of similar chemical/biologic 
composition to ALA. 
3.2.3
Personal or family history of porphyria
3.2.4
Uncontrolled concurrent illness including but not limited to: ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness//social situations that would limit compliance 
with study requirements
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3.2.5
Women who are pregnant or become pregnant will be excluded from the trial as 
it is unknown if ALA is teratogenic or has abortifacient effects. Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with 5-ALA breastfeeding should be discontinued if the 
mother is treated with 5-ALA.
3.2.6
Prior history of GI perforation, diverticulitis, and or/peptic ulcer disease
4.0
TREATMENT PLAN
4.1
Treatment Dosage and Administration
4.1.1
Treatment will be administered on an inpatient basis. This does not pose a 
financial burden to the subject as pre-operative care provides for admission to 
hospital. One-time, single-dose oral administration of Gleolan® (5-ALA) is 
planned (20mg/kg). No investigational or commercial agent or therapies other 
than those described below may be administered with the intent to treat the 
patient’s malignancy prior to surgery and patients will not be part of any other 
clinical trial at the time of this surgery for anything, not just the identified, 
malignant tumor.
4.1.2
Gleolan® (5-ALA) 20mg/kg will be reconstituted in the minimum volume of sterile 
water and may be mixed with a clear liquid or apple fruit juice before being 
administered in a single oral dose approximately 3 hours (3-5h) prior to 
scheduled surgery. This one-time single dose administration precludes the need 
for intra-patient dose modification or delay. In the event of emesis of the product, 
the dose will not be repeated.
Gleolan® (5-ALA) is presented as a powder for oral solution in 60 ml colorless 
glass vials. The formulation contains 1.5 g 5-aminolevulinic acid hydrochloride 
corresponding to 1.17 g of 5- aminolevulinic acid. No other ingredients are used 
besides the clear liquid or apple juice used to mix with at time of consumption. 
No impurities have been identified. Details on the manufacturing method, 
validation of the process as well as in process controls are available and are on 
file with the FDA. The drug product is manufactured according to a documented, 
validated process that has given comparable results in the production of both 
pilot and large scale batches. The specification and release tests for the drug 
product are in compliance with both Pharmacopia European and current 
guidelines. Where applicable, analytical validation has been performed. 
Limits for impurities and possible degradation products are set according to the 
results reported for the batches used for relevant toxicological and clinical testing 
taking into account the proposed route of administration as well as the relevant 
guidelines. The specifications and the routine release tests are adequate to 
control the quality of the drug product and are on file with the FDA. Stability test 
results after 36 months storage justify a shelf-life of 36 months when stored at 
25°C ± 2°C. After reconstitution, the in-use shelf-life is 24 hours when the 
solution is stored at room temperature. In conclusion, the data are complete and 
satisfactory, ensuring the reproducible manufacturing of a product of good 
quality. 
The specification and release tests for the drug substance are in compliance with 
Pharmacopia European and current guidelines. The analytical methods are either 
pharmacological methods or well validated. Stability results after both 
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accelerated and long term testing indicate that the drug substance 5-
aminolevulinic acid hydrochloride can be considered stable. The stability data 
support a satisfactory retest period of 3 years when stored at -20 °C in the 
proposed container. The aseptic manufacturing process of the drug product 
consists of four steps: compounding, filtration, filling and lyophilisation. The 
validation of the manufacturing process is satisfactory and relevant in-process 
controls are performed. The synthesis of the drug substances consists of three 
stages, for which the potential content of each vial is intended to be reconstituted 
in 50 ml water or apple juice. One ml of the reconstituted solution contains 23.4 
mg of 5-aminolevulinic acid, corresponding to 30 mg 5-aminolevulinic acid 
hydrochloride. The closure consists of colorless glass vial (Type II, Ph Eur) and 
bromobutyl-rubber stopper 20 mm (Type I, Ph Eur) and a flip cap top. 
The oral solution is intended for single (partial) use. 5-aminolevulinic acid 
hydrochloride is administered orally to adult patients with head and neck 
malignancy prior to tumor removal by surgery. 5- Aminolevulinic acid is a prodrug 
that is metabolized intracellularly to form the fluorescent molecule protoporphyrin 
(PPIX), which is selectively accumulated in tumor cells and epithelial tissue. 
Following excitation with blue light (λ = 400 – 410 nm) the PPIX, which has 
accumulated selectively in the malignant tissue, the tumor emits a red-violet light 
(red-light fluorescence). Tumor resection is extended as the surgeon is able to 
identify malignant tissue as differentiated from normal tissue after administration 
of 5-aminolevulinic acid (Stummer et al. 2006, 2010).
4.2
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 Time and Events 
table (See section 5.4). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity. 
4.3
Concomitant Medications/Treatments
Compounds of similar chemical/biologic composition to 5-ALA are prohibited. Patients 
should refrain from use of other phototoxic substances (e.g. tetracyclines, sulfonamides, 
fluoroquinolones, hypericin extracts) for 72h after administration. Patients should avoid 
exposure of eyes and skin to strong light sources (e.g. operating illumination, direct 
sunlight or brightly focused indoor light) for 24h after 5-ALA administration. Patients 
should not be exposed to any photosensitizing agents up to 2 weeks after 5-ALA 
administration.
Within 24h after 5-ALA administration, other potentially hepatotoxic medicinal products 
should be avoided.
In patients with pre-existing cardiovascular disease, concomitant blood pressure 
medications should be used cautiously as 5-ALA has been shown to decrease systolic 
and diastolic blood pressure, pulmonary artery systolic and diastolic pressure, and 
vascular resistance.
4.4
Other Modalities or Procedures
Fluorescence-guided resection will be performed using the standard surgical operating 
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microscope. The surgical operating microscope will be adapted with a filter set intended 
to visualize fluorescence excitation in the wavelength range from 390nm to 440nm and 
for observation in the 600-700nm range. The adaptation includes standard white light 
emission source and a combination of excitation and observation low and high pass 
optical filters with slightly overlapping transmission integrated into their optical 
configuration. The proposed filter set is commercially available globally. A small fraction 
of excitation light is remitted from the tissue, which then generates a blue tone contrast 
from the healthy brain anatomy in contrast to the bright red, 5-ALA induced PPIX 
fluorescence. Thus, there are two light sources to illuminate the resected field: White light 
phase and Blue light phase. During the white light illumination, an attenuator reduces 
irradiance to approximately 50% to minimize the need for illumination adjustment. During 
the blue light phase, an electromagnetic filter switch is used to introduce a dielectrically 
coated observation filter with a 600-700nm wavelength into the light paths of the surgical 
microscope. These filters transmit tumor associated red PPIX fluorescence and a portion 
of backscattered normal tissue blue excitation light which does not fluoresce. A camera 
system on the microscope is used to record 5-ALA/PPIX red fluorescence.
Gleolan® (5-ALA) will be reconstituted in the minimum volume of sterile water and may 
be mixed with a clear liquid or apple fruit juice before being given orally approximately 3 
hours (3-5h) prior to scheduled surgery. Image-guided microsurgical resection of the 
tumor will be undertaken as per operator preference. Following standard surgical entry, 
further tumor resection will be performed by switching to the microscope fluorescence 
‘blue light’ mode.
Photographs will be taken during the ‘blue light’ imaging to provide identification of optical 
fluorescent tumor. Images will be taken before, during and after resection to capture 
tumor fluorescence. All tumor specimens will be sent to pathology for frozen examination 
as per institutional standard of care. Any tissue specimens from the fluorescent areas will 
be photographed and sent for permanent histopathologic examination and molecular 
genetic analysis to confirm the presence of malignant tumor. The intraoperative pictures 
of the resection cavity in the ‘blue light’ mode will be analyzed to provide confirmation of 
tissue/tumor fluorescence associated with tumor resection. The surgeon will document 
whether visualization of fluorescence was present with each of the labeled tissue 
specimens. The remainder of the resection will be performed with the ability to switch 
between white light and blue light as chose by the surgeon. If no fluorescence is 
observed in the resection site it will be noted, but will otherwise undergo identical tumor 
resection, photography and histopathologic examination.
Pathologic confirmation of tumor type will be made by a pathologist who will not be 
informed of the fluorescence status of the tissue samples. Histopathology will 
characterize the resected tissue as
(1) Diagnostic tissue or not
(2) Presence of malignant tumor cells
(3) Pathologic grading and tumor type
Genetic testing will be performed in accordance with standard of care at the testing 
institution for the tumor specimens.
4.5
Duration of Therapy
One-time, single dose administration of oral Gleolan®(5-ALA) (20mg/kg) is planned 3-5h 
prior to induction of anesthesia. However, surgery can be initiated up to 8 hours after 
dosing. In the event of allergic reaction, other severe adverse effect, or changes in the 
patient’s condition prior to surgery rendering the patient unacceptable for further 
treatment in the judgement of the investigator, or patient decides to withdraw from the 
study, the therapy protocol will be ended and fluorescent-guided surgery will not proceed.
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4.6
Duration of Follow Up
Analysis of progression and correlative studies will be performed as per standard of care 
for 6 weeks post-surgery. Follow-up will consist of 3 time points: within 48h post-surgery, 
a 2 week and a 6 week postoperative office visit. Patients removed from treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.
4.7
Removal of Patients from Protocol Therapy
Patients will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the patient was removed in the Case Report Form. The patient should be followed-up per 
protocol. 
4.8
Patient Replacement
Patients who withdraw from the study will be replaced through further recruitment at 
clinical sites to meet target recruitment goals.
5.0
STUDY PROCEDURES
5.1 Screening/Baseline Procedures (60-0 days before surgery)
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 prior to registration unless otherwise stated. 
The screening procedures include:
5.1.1
Informed Consent
5.1.2
Medical history
Complete medical and surgical history, history of infections
5.1.3
Demographics
Age, gender, race, ethnicity
5.1.4
Review subject eligibility criteria
5.1.5
Review previous and concomitant medications
5.1.6
Physical exam including vital signs, height and weight
Vital signs (temperature, pulse, respirations, blood pressure), height, weight
5.1.7
Performance status
Performance status evaluated prior to study entry according to Appendix A.
5.1.8
Adverse event assessment
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting.
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5.1.9
Hematology
Complete Blood Count (CBC) to include: white blood cells (WBC), red blood 
cells (RBC), hemoglobin (HGB), hematocrit (HCT) , MCV, MCHC, WBC 
differential, platelet count.
5.1.10
Serum chemistries
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin.
5.1.11
Pregnancy test (for females of child bearing potential)
Will be performed prior to 5-ALA administration preoperatively as standard 
operating procedure for all surgical patients.
5.1.12
Tumor assessment
Standard of care pre-operative imaging will be conducted as part of usual 
surgical planning.
5.2
Procedures During Treatment
5.2.1
Day 0 (Day of Surgery) 5-ALA Administration

Physical exam, vital signs

Administration of 5-ALA 3h prior to surgery- single dose oral 20mg/kg

Monitoring for adverse events
5.2.2
Day 0 (Day of Surgery) Fluorescence-Guided Surgery

Intraoperatively, blue light microscopy will be used to visualize tumor. 

Images will be captured during resection, and surgeon will assign subjective 
fluorescence scores of no brightness (0), mild brightness (1-pink), moderate 
brightness (2-orange) or robust brightness (3- lava-like orange). Fluorescence 
homogeneity or heterogeneity will be noted. After excision the tumor will again 
undergo imaging to characterize 5-ALA fluorescence and homogeneity or 
heterogeneity. 

Patient vital signs will be monitored and recorded throughout surgery. 

Following pathology analysis, tumor classification will be recorded. 
Histopathologic examination of tumor specimens will be correlated with 
fluorescence on intraoperative imaging. Morphological factors such as tissue 
cellularity, cytological atypia, nuclear hyperchromasia, as well as tumor 
markers and immunostaining will be examined. Presence of positive or 
negative surgical margins will be recorded.

5-ALA sensitivity, specificity, positive predictive value and negative predictive 
value will be determined for different tumor types and histopathology based on 
correlation of intraoperative fluorescence with tumor pathology.
5.2.3
Within 48h after treatment termination

Physical exam, vital signs

Monitoring for adverse effects
5.3
Follow-up Procedures
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5.3.1
Patients will be followed at designated time points of within 48h, 2 weeks, and 6 
weeks postoperatively for regular post-surgical examinations. Recorded at these 
visits:

Physical exam, vital signs

Concurrent medications

Adverse events
5.4 Time and Events Table
Study 
Assessment or 
Procedure
Baseline 
(-60 to 
day 0 
before 
surgery)
Day 0 (At 
5-ALA 
administr
ation)
Day 0 
(prior to 
surgery)
Within 
48h of 
surgery
Week 2
Week 6
Informed 
Consent
X
Demographics 
and Medical 
History
X
X
X
X
Physical Exam 
(vitals, weight, 
Karnofsky status)
X
X
X
X
X
Concurrent 
Medications
X
X
X
X
X
X
Adverse Events 
Evaluation
X
X
X
X
X
X
Tumor Imaging
X
Pregnancy testd
X
Other labs (CMP, 
CBC, GGT)a,b,c
X
X
X
X
Gleolan® (5-
ALA)e
X
a.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium, total protein, SCOT (AST), SCPT (ALT), sodium, gamma glutamyl 
transpeptidase (GGT)
b.
Phosphorus, uric acid, creatinine kinase, and amylase will be added as clinically 
necessary/indicated.
c.
Repeat only those labs that remain abnormal after 6 weeks unless attributed to other therapy
d.
Pregnancy test (women of childbearing potential)- part of standard pre-operative protocol
e.
Gleolan® (5-ALA) is dosed as 20mg/kg. Oral administration is one-time only and based on 
actual weight on day of surgery.
5.5 Removal of Subjects from Study
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include:
5.5.1
Patient voluntarily withdraws from treatment (follow-up permitted); 
5.5.2
Patient withdraws consent (termination of treatment and follow-up);
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5.5.3
Patient is unable to comply with protocol requirements;
5.5.4
Patient demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator);
5.5.5
Patient experiences toxicity that makes continuation in the protocol unsafe;
5.5.6
Treating physician judges continuation on the study would not be in the patient’s 
best interest;
5.5.7
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event);
5.5.8
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study;
5.5.9
Lost to follow-up. If a subject cannot be located to document status after a period 
of 2 months postoperatively, the subject will be considered lost to follow-up. All 
attempts to contact the subject during this time period will be documented. 
6.
ADVERSE EVENTS
6.1
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 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. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
6.2
Definitions
6.2.1
Definition of Adverse Event
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 an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. The occurrence of an AE may come to the attention of study 
personnel during study visits and interviews or by a study participant presenting 
for medical care. Adverse events will be coded in accordance with the CTCAE 
V4.0. For analysis of adverse events, AEs will be obtained at the time of 
ingestion of the investigational product before surgery, during the first 48 hours, 2 
weeks and 6 weeks after surgery. In addition, serious adverse events (SAE) will 
be collected beginning from the time the subject signs consent. All AEs must be 
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graded for intensity and relationship to study product. The investigator is 
responsible for recording all AEs that are observed during this study according to 
the definition.
6.2.2
Severity of Adverse Events
If possible, all AE will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 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.
6.2.3
Serious Adverse Events
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that:
6.2.3.1
Results in death.
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself.
6.2.3.2
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).
6.2.3.3
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
6.2.3.4
Results in persistent or significant disability or incapacity.
6.2.3.5
Is a congenital anomaly/birth defect
6.2.3.6
Is an important medical event
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 a serious adverse event. 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.
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6.3
Steps to Determine If an Adverse Event Requires Expedited Reporting
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4). 
Step 2: Grade the adverse event using the NCI CTCAE v4.
Step 3: Determine whether the adverse event is related to the protocol therapy 
Attribution categories 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.
-
Unrelated – The AE is clearly NOT related to the study treatment.
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly.
Step 4: Determine the prior experience of the adverse event. 
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 Information Section of this 
protocol;

the drug package insert;

the current Investigator’s Brochure
6.4
Reporting Requirements for Adverse Events
6.4.1
Expedited Reporting

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. 

The IRB/PPHS must be notified within 5 business days of “any 
unanticipated problems involving risk to subjects or others” (UPR/UPIRSO).
The following events meet the definition of UPR
a.
Any new information that indicates a new or increased risk, or 
safety issue (e.g., interim analysis, safety monitoring report, 
publication, updated sponsor safety report), that indicates an 
unexpected change to the risk/benefit ratio for the research.
b.
An investigator brochure, package insert, or device labeling is 
revised to indicate an increase or magnitude of a previously 
known risk, or describes a new risk. 
c.
Withdrawal, restriction, or modification of a marketed approval of 
a drug, device, or biologic used in research protocol
d.
Protocol deviation or violation that harmed subjects or others or 
that indicated subjects or others might be at increased risk of 
harm.
e.
Complaint of subject that indicates subjects or others might be at 
increased risk of harm or at risk of a new harm
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f.
Any breach in confidentiality that may involve risk to the subject 
or others.
g.
Any harm experienced by a subject or other individual that in the 
opinion of the investigator is unexpected and at least probably 
related to the research procedures.
6.4.2
Routine Reporting
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation- are to be reported annually as part 
of regular data submission.
Those AEs that do not require expedited reporting are reported in routine study 
data submissions. Expected AEs such as Grade 1 and 2 Skin Reactions, 
AST/ALT elevation, Grades 1 and 2, nausea/vomiting will not be reported in an 
expedited fashion. If the subject has an elevated GGT at the time of study entry, 
but has normal ALT and AST, reporting will not be required unless the grade has 
increased by 2 levels.
6.5
Stopping Rules 
If patients exhibit respiratory distress or serious allergic reaction following 5-ALA 
administration, their participation in the study will cease
Stopping rules for trial enrollment have been incorporated into the protocol based on liver 
function tests (LFTs). The extensive European experience with Gleolan® and 
fluorescence- guided tumor resection has shown that patients very commonly have a 
transient increase in their liver enzymes (>=1/10). Peak values occur between 7 and 14 
days after administration. However, LFT increases can occur up to 6 weeks after 
administration. The liver toxicity data available from the Phase III European trial 
(Stummer 2006) has shown that after 6 weeks, the incidence of Grade 3 and Grade 4 
events (>5-10x or >10x upper limit of normal) occur in less than 6% of patients for 
ALT/GPT, AST/GOT, and Gamma-GT (GGT) liver testing.36 Approximately 10% had 
Grade 3 or 4 elevations in GGT at 7 days; 5% had Grade 3 or 4 elevations in GGT at 6 
weeks, and 1% had persistent ALT or AST elevations at 6 weeks. LFTs returned to 
normal in all patients. In both groups of patients from the European phase III trial, 
(Gleolan® and placebo control), 1 patient developed a hepatic serious adverse event 
(SAE). The Gleolan® patient developed cholelithiasis. 
Patients will be continuously monitored for sustained Grade 3 or 4 elevations in their 
LFTs at six weeks following Gleolan® administration. A comprehensive metabolic serum 
panel, including albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, potassium, total protein, SGOT[AST], SGPT[ALT], sodium, 
gamma glutamyltranspeptidase (GGT), will be obtained prior to surgery, within 48 hours 
of surgery, 2 weeks, and 6 weeks after surgery. These tests will only be repeated after 6 
weeks if SGOT[AST], SGPT[ALT], and gamma glutamyltranspeptidase (GGT) remain 
elevated after 5-ALA dosing. 
We will continuously monitor the rate of sustained Grade 3 or 4 elevations in LFTs at 6 
weeks following Gleolan® administration and accrual will be halted if there is sufficient 
evidence that the sustained Grade 3 or 4 LFT elevation rate exceeds the acceptable rate 
of 5% by more than 5% (unacceptable rate 10%). If the cumulative number of patients 
that experience grade 3 or 4 elevations in the LFTs at 6 weeks from drug administration 
is greater than the associated boundary value bk listed in the table below, among the k 
patients enrolled in the trial, enrollment in the trial will be halted for safety considerations 
prompting IRB notification and a DSMB meeting will be requested. 
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# of accrued 
subjects, k
2-9
10-20
21-23
Boundary, bk
1
2
3
The following table shows the probability of early stopping if the true rates of sustained 
grade 3 or 4 elevations in the LFTs are at or lower than 10%. For safety of the 
participants, we would like to have a low probability of early stopping if the sustained LFT 
rates are low, but high probability of early stopping if the sustained LFT rate is high.
Probability of early stop based on true grade 3 or 4 LFT rate
True SAE rate
5%
6.2%
7.5%
8.8%
10%
Probability of early stop
0.15
0.21
0.28
0.36
0.44
This stopping rule was computed using the toxbdry function in R and calculations of this 
function are based on methods described in Chapter 12 of Jennison and Turnbull39 and in 
the illustrative paper by Ivanova, Qaquish and Schell40. 
toxbdry(0.05,0.10,c(1:23),cP0=0.15,cP1=0.30,ngrid=5)
7.0
DRUG INFORMATION
7.1    Gleolan®
7.1.1
Description and Composition 
Gleolan® is available in colorless glass vials containing 1.5 g 5-aminolevulinic acid 
hydrochloride (Gleolan®) corresponding to 1.17 g of 5-aminolevulinic acid (5-ALA) No 
other ingredients are used. The closure consists of colorless glass vial (Type II, Ph Eur) 
and bromobutyl-rubber stopper ø 20 mm (Type I, Ph Eur) and flip cap. The powder for 
oral solution is intended for single (partial) use. To prepare the ready-to-use solution the 
content of one vial is dissolved in 50 ml of water or apple juice. The concentration of the 
reconstituted solution is 3%. Gleolan® is administered orally to patients prior to tumor 
removal by surgery (20 mg/kg BW). The reconstituted solution may be prepared up to 24 
hours prior to use if protected from light. It should be given  hours (range 3-5 hours) prior 
to planned induction of anesthesia for surgery, although its effect is present for up to 8-12 
hours. This step is critical for an optimal visualization of tumor tissue due to 
pharmacokinetic properties of Gleolan®. Tumor resection is improved since malignant 
tissue can be differentiated more easily from normal tissue after administration of 
Gleolan® following excitation with blue light (λ = 400 - 410 nm) in malignant tissue. The 
rationale for the development of a powder for oral solution is rapid onset of action and 
individual dosage of the drug product compared to slower onset of action and less flexible 
dosing of conventional tablets/capsules. 
7.1.2 Manufacture 
Name and address of the manufacturer responsible for batch release: 
IDT Biologika GmbH
Am Pharmapark
Dessau-Rosslau, 06861, Germany (DEU)
Manufacturing process 
The manufacturing process briefly consists of the dissolution preparation, sterile filtration 
(0.45 followed by 0.22 microns) aseptic filling and assembling process and lyophilization. 
Evaluation of critical manufacturing steps is available together with In-Process Controls 
and Process Validation Data. These are all considered to be satisfactory. 
7.1.3 Control of Excipients 
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The only other ingredient (water for injection) conforms to the specification in Ph Eur. The 
documented certificates of analysis verify conformance of the specified parameters. 
7.1.4 Product Specification 
The product specification is simple and includes relevant tests by validated methods for 
identity (IR/HPLC), assay (HPLC), clarity, color, purity (degradation products by HPLC), 
water content (Ph Eur), sterility (Ph Eur), endotoxins, pH, particulate matter, residual 
solvents (GC), etc. Batch analyses show good uniformity and compliance with the agreed 
specification. Data is on file with the FDA. 
7.1.5 Container Closure System 
The product is a sterile lyophilized preparation in colorless glass vials, containing 1.5 g 
Gleolan® (corresponding to 1.17 g. 5-ALA). The closure consists of colorless glass vial 
(Type II, Ph Eur) and bromobutyl-rubber stopper ø 20 mm (Type I, Ph Eur) and flip cap. 
Batch results comply with the respective specifications. 
7.1.6 Stability 
Stability studies have been performed taking the relevant guidelines into account. Thirty-
six (36) months of stability data are provided for lyophilized preparation batches stored at 
25ºC/60%RH and six months of stability data are provided for the lyophilized preparation 
stored at the accelerated condition of 40ºC/75%RH. The results of the stability analyses 
support the shelf life and storage conditions as defined in the package insert. 
Furthermore, in use stability has been investigated. The content of one vial was dissolved 
in water as recommended for the drug product and stored for 24 h. The parameters 
investigated are identical to the parameters investigated for the lyophilisate. All results 
obtained meet very well with the specification set for the drug product. 
The Investigator, or a responsible party designated by the Investigator, will maintain a 
careful record of the inventory and disposition of all agents.
7.1.7 Side Effects
Side effects include nausea, GI upset, hypotension, photosensitivity and elevation of liver 
enzymes. See section 1.2.3 for full side effect and toxicity profile.
8.0
STATISTICAL CONSIDERATIONS
8.1
Study Design/Study Endpoints
This is a single center, single arm pilot study conducted at the Mount Sinai Health 
System with 23 subjects planned for enrollment. The aim is to examine feasibility of 5-
ALA (Gleolan®) use as an adjunct diagnostic imaging tool to detect malignant tumor 
tissue in head and neck and skull base cancer patients. Eligible patients will take 5-ALA 
3h prior to surgery with single oral dose of 20mg/kg. The standard surgical procedure will 
be conducted accompanied by the intra-operative blue light microscopic image for 
surgeons to assign PPIX tissue fluorescence scores of no brightness (0), mild brightness 
(1-pink), moderate brightness (2-orange) or robust brightness (3- lava-like orange). The 
resected tissues will be examined by pathologists to confirm presence of cancer cells.    
8.2
Sample Size and Accrual
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There is no previous publication for applying 5-ALA to head and neck cancer patients. 
The sample size calculation is based on the experience of 5-ALA in brain cancer. A 
literature review study summarized the usage of 5-ALA in patients with malignant 
Gliomas between 2000 and 2015.3 The sample sizes in the studies included in the review 
ranged from 11 to 97. The sensitivity ranged from 75% and 95% while the specificity 
ranged from 53% to 96%. In our study, all tissue samples will be collected from the head 
and neck cancer patients undergoing standard of care surgical resection. The surgeons 
will provide the pathologists with the patient resected specimen marked, typically in 4 
different regions with 3 regions located within the tumor region and 1 located at the 
boundary or outer region of the tumor. Each region will be marked according to the 
associated intensity of the PPIX tissue fluorescence score at that location as no 
brightness (0), mild brightness (1-pink), moderate brightness (2-orange) or robust 
brightness (3- lava-like orange).  Thus each patient is expected to contribute 1 tissue 
sample from a normal margin region and 3 tissue samples from the tumor tissue region at 
a ratio of 1:3 (i.e. the pathologists will examine the samples from each patient 
histopathologically), which translates to a tumor tissue prevalence of 75% in the overall 
tissue samples.
The following calculations were performed using PASS 15 Power Analysis and Sample 
Size Software (2015). NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass and 
using the methods for calculating sample size for co-primary endpoints of sensitivity and 
specificity.41-43  
Assuming a prevalence of 75% and a sample sensitivity of 85%, the sample size needed 
to estimate a two-sided 95% sensitivity confidence interval with a width of at most 35% (± 
17.5% precision assuming asymptotic with continuity correction method) is at least 23.We 
will use a sample size of 23 in this study. 
If the prevalence is as low as 50% in our sample then the width of our 75% sensitivity 
confidence interval will increase to 40.6% (±20.3 precision) which still gives a lower 
bound for the CI above 50%. 
The sample size calculation is performed conservatively assuming only 1 measure per 
patient, but there will be typically 4 per patient which will improve precision of estimates.
We expect to enroll the necessary patients in 6 months at a rate of approximately 4 
patients per month. This accrual rate is based on historical monthly rates of surgery in 
this patient population at the Mount Sinai hospital. 
8.3
Data Analyses Plans
The characteristics of participants and information collected before 5-ALA is administered 
will be summarized using standard statistics, such as mean, SD, median, 1st and 3rd 
quartiles for continuous variables, and count, percentage for categorical variables.
Analysis of the primary endpoint
To assess the feasibility of using 5-ALA as an adjunct diagnostic imaging tool to detect 
malignant tumor tissue, the point estimate of sensitivity will be computed according to the 
following definition:
Sensitivity: proportion of tumor tissues that tested positive on 5-ALA induced 
fluorescence.
The definition of a positive test is the fluorescence score equal to or greater than 
1 while a negative test is considered a score of 0. For the assessment of sensitivity and 
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specificity, histological diagnoses of any upper aerodigestive head and neck cancer in 
addition to squamous cell carcinoma, carcinoma in situ, and severe and moderate 
dysplasia were classified as malignant, whereas light dysplasia and normal tissue will be 
classified as benign by pathologists. The analysis population includes all patients who 
sign the inform consent regardless of taking 5-ALA or not. Each patient is expected to 
contribute multiple samples and the pathologists will determine presence of malignancy 
in each sample. A contiguous table (fluorescence scores vs. pathological results) that 
presents the frequency and percentage of each cell will be prepared. A generalized 
estimating equation (GEE) model accounting for repeated measure within each patient 
will be used to estimate the sensitivity and specificity.44-45 For sensitivity and specificity, 
the dependent variable is the PPIX fluorescence test result (positive vs. negative) and the 
independent variable is presence of tumor cells (tumor vs. normal). 
Analysis of the secondary endpoints
To further determine the diagnostic performance of 5-ALA for detecting of malignant 
tumor tissue, specificity, PPV and NPV will be computed. Specificity will be computed 
according to the following definition:
Specificity: proportion of normal tissues that tested negative on 5-ALA induced 
fluorescence.
The definition of a positive test is the fluorescence score equal to or greater than 1 while 
a negative test is considered a score of 0. For the assessment of sensitivity and 
specificity, histological diagnoses of any upper aerodigestive head and neck cancer in 
addition to squamous cell carcinoma, carcinoma in situ, and severe and moderate 
dysplasia were classified as malignant, whereas light dysplasia and normal tissue will be 
classified as benign by pathologists. The analysis population includes all patients who 
sign the inform consent regardless of taking 5-ALA or not. Each patient is expected to 
contribute multiple samples and the pathologists will determine presence of malignancy 
in each sample. A contiguous table (fluorescence scores vs. pathological results) that 
presents the frequency and percentage of each cell will be prepared. A generalized 
estimating equation (GEE) model accounting for repeated measure within each patient 
will be used to estimate the sensitivity and specificity.44-45 For sensitivity and specificity, 
the dependent variable is the PPIX fluorescence test result (positive vs. negative) and the 
independent variable is presence of tumor cells (tumor vs. normal). 
For PPV and NPV, a generalized estimating equation (GEE) model accounting for 
repeated measure within each patient will be used. The dependent variable is presence 
of tumor, and the independent variable is the test result. The point estimate along with a 
corresponding two-sided 95% confidence interval will be provided using PROC 
GENMOD.    
The 5-ALA related adverse events will be recorded using standardized toxicity criteria 
and known side effect profile. Frequency of each observed adverse event will be 
calculated at each monitor time point. The rate of each adverse effect will be estimated 
as the number of adverse events within 6 weeks after surgery divided by the number of 
person days followed. The point estimate of the incidence rate along with a 
corresponding two-sided 95% confidence interval will be provided using PROC 
GENMOD.46 
The analyses will be conducted using SAS 9.4 software. Copyright ©[2002-2012] SAS 
Institute Inc.
  
9.0
STUDY MANAGEMENT
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9.1
Conflict of Interest
Any research personnel who has a conflict of interest with this study (patent ownership, 
intellectual property, royalties, or financial gain greater than the minimum allowable by 
their institution, etc.) must declare their conflict of interest to the appropriate institutional 
review bodies. Local institutional conflict of interest policies will be followed for all 
research personnel associated with the research project.  
9.2
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
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.
9.3
Required Documentation 
(For Cancer Clinical Trials Office Managed Studies multi-site studies)
Before the study can be initiated at any site, the following documentation must be 
provided to the CCTO by all sites.

A copy of the official IRB approval letter for the protocol and informed consent

IRB membership list

CVs and medical licensure for the principal investigator and any associate
investigators who will be involved in the study

A copy of the IRB-approved consent form

CAP and CLIA Laboratory certification numbers and institution lab normal values

Executed clinical research contract (if applicable)
9.4
Registration Procedures
Treatment Trials utilizing biologics, drugs, or devices must register subjects through the 
Cancer Clinical Trials Office Subject Central Registration process.  Include the following 
boilerplate language:
All patients must be enrolled onto trial through the Cancer Clinical Trials Office Central 
Registration process. Prior to registration, a member of the study staff must scan and 
email the following documents as individual PDF files to the Central Registration Mailbox 
(central.registration@mssm.edu) with a cc to the Central Registrars. 

Signed Informed Consent(s)
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25

Signed CCTO Registration Form

Signed Eligibility Checklist

Additional supporting documentation (i.e. lab/scan reports) may be included at the
study teams’ discretion.
The designated Central Registrar will review all received documents for consistency and 
completeness. 

If there is any concern or discrepancy noted, the study staff member who originated
the central registration request will be contacted immediately for clarification.
If the patient is deemed eligible for study enrollment based on a thorough review 
by the Central Registrar, the patient will be entered into the CTMS system and a 
Registration Confirmation Letter is generated and sent to the following individuals:

Study team

Treating Physician

Research Infusion Nurse designee

Research Pharmacy
9.5
Data Management and Monitoring/Auditing
11.5.1 Elements of a Data and Safety Monitoring Plan
List the name(s) of the individual(s) at the Icahn School of Medicine at Mount Sinai 
(ISMMS) who will be responsible for data and safety monitoring of this study. For each 
individual, indicate their role, name, title, and department information. 
ISMMS Principal Monitor:
Principal Investigator
Last Name: Iloreta
First Name: Alfred-Marc
Academic Title: Assistant Professor
Department: Otolaryngology
Mailing Address: 
1 Gustave L Levy Place
10th Floor
New York, NY 10020
Phone: Office 212-241-9410
E-mail: Alfred-Marc.Iloreta@mountsinai.org
ISMMS Additional Monitors:
Co-Investigator
Last Name: Bederson
First Name: Joshua
Academic Title: Professor and Chair
Department: Neurosurgery
Mailing Address: 
Mount Sinai Hospital
Annenberg Building
1468 Madison Avenue
Floor 8, Room 28
Phone: Office 212-241-2377
E-mail: joshua.bederson@mountsinai.org
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Last Name: Shrivastava
First Name: Raj
Academic Title: Professor
Department: Neurosurgery
Mailing Address: 
Mount Sinai Hospital
Annenberg Building
1468 Madison Avenue
Floor 8, Room 35
Phone: Office 212-241-6147
E-mail: raj.shrivastava@mountsinai.org
Dr. Iloreta will be the principal monitor for this study. The majority of study patients will be 
under his care. He will be best positioned to assess and respond to any adverse events 
that are reported.
Patients will be monitored for adverse events as described in section 6. All adverse 
events will be collected from the time of drug administration until 6 weeks after surgery. In 
addition, SAEs will be collected beginning from the time the subject signs consent. The 
description and grading scales found in the revised NCI Common Terminology Criteria for 
adverse events (CTCAE) version 4.0, which will be utilized for adverse event reporting 
are available online at http://ctep.cancer.gov/reporting/ctc.html. Expected adverse events 
specific for Gleolan® are listed in section 1.2.
Safety and data information will be reviewed by the monitors every 6 months.
See section 6.6 stopping rules.
As described previously, dose selection for Gleolan® is 20mg/kg based on previous 
studies.
National Cancer Institute Common Toxicity Criteria will be used to evaluate adverse 
events as described in section 6.
Data will be recorded in patient binders and secure Mount Sinai redcap storage, ensuring 
completeness and accuracy through redundancy. Data will also be checked at set 
intervals by the DMC.
If temporary or permanent suspension of the study occurs, in addition to PPHS the 
occurrence will be reported to the IRB.
8.5.2 Data Monitoring Committee/Data Safety Monitoring Board (DMC/DSMB)
9.6
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, the study shall be 
conducted exactly as described in the approved protocol. 
9.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
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9.6.2
Other Reportable New Information and Protocol Deviations/Violations
In accordance with local IRB requirements, the following information must be reported 
within five (5) business days. 

Non-compliance with federal regulations governing human research or with the
requirements or determinations of the IRB, or an allegation of such non-compliance

Failure to follow the protocol due to the action or inaction of the investigator or
research staff.

Breach of confidentiality

Premature suspension or termination of the research by the sponsor or
investigator.
9.7
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 
IRB for approval prior to implementation. 
9.8
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 six years after the completion and final study 
report of this investigational study.
9.9
Obligations of Investigators
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.
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10.0
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laryngeal lesions. Eur Arch Otorhinolaryngol 264, 621-626, doi:10.1007/s00405-007-0251-y 
(2007). 
33 Poh, C. F. et al. Fluorescence visualization detection of field alterations in tumor margins of oral 
cancer patients. Clin Cancer Res 12, 6716-6722, doi:10.1158/1078-0432.CCR-06-1317 (2006). 
34 Nguyen, P. et al. High specificity of combined narrow band imaging and autofluorescence mucosal 
assessment of patients with head and neck cancer. Head Neck 35, 619-625, 
doi:10.1002/hed.22999 (2013). 
35 Wu, C., Gleysteen, J., Teraphongphom, N. T., Li, Y. & Rosenthal, E. In-vivo optical imaging in head and 
neck oncology: basic principles, clinical applications and future directions. Int J Oral Sci 10, 10, 
doi:10.1038/s41368-018-0011-4 (2018).
36 Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for 
resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 
2006; 7:392-401. PMID: 16648043
37 Webber, J. et al. Side Effects and Photosensitization of Human Tissues after Aminolevulinic Acid,
Journal of Surgical Research 69(1): 31-37, https://doi.org/10.1006/jsre.1997.5004.
38 Nabavi A, Thurm H, Zountsas B, et al. Five-aminolevulinic acid for fluorescence-guided resection of 
recurrent malignant gliomas: a phase II study. Neurosurgery 65(2009) 1070-1076; discussion 
1076-1077.
39 Jennison, C. and BW Turnbull. 2000. Group Sequential Methods with Applications to Clinical Trials. 
London, New York: Chapman and Hall/CRC.
40 Ivanonva, Anastasia, Bahjat F. Qaqish, and Michael J. Schell. 2005. “Continuous Toxicity Monitoring in 
Phase II Trials in Oncology.” Biometrics 61(2)”: 540-45.
Effective Date: 12/20/2024
End Date:12/19/2025


STUDY-20-00713
________________________________________________________________________
30
41 Hajian-Tilaki, K. 2014. Sample Size Estimation in Diagnostic Test Studies of Biomedical Informatics. 
Journal of Biomedical Informatics, 48 pp 193-204
42 Fleiss, J.L., Levin, B., Pain, M.C. 2003. Statistical Methods for Rates and Proportions. Third Edition. 
John Wiley & Sons. New York.
43 Newcombe, R. G. 1988. Two Sided Confidence Intervals for the Single Proportion: Comparison of Seven 
Methods. Statistics in Medicine, 17, pp. 857-872.
44 Genders TSS, Spronk S, Lesaffre E. Sensitivity and Specificity of Clustered Data: A Tutorial 1. Radiology 
2012; 265(3):910-916. Doi: 10.1148/radiol.12120509/-/DC1.
45 Sternberg MR, Hadgu A. A GEE Approach to Estimating Sensitivity and Specificity and Coverage 
Properties of the Confidence Intervals. Stat Med. 2001;20(9-10):1529-1539. Doi:10.1002/sim.688.
46 Boshuizen HC, Feskes EJ. Fitting Additive Poisson Models. Epidemiol Perspect Innov. 2010; 7(1): 4
Effective Date: 12/20/2024
End Date:12/19/2025


STUDY-20-00713
________________________________________________________________________
31
11.0
APPENDICES
APPENDIX A
Performance Status Criteria
Karnofsky performance scale
Percent
Description
100
Normal, no complaints, no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
80
Normal activity with effort; some signs 
or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance but is 
able to care for most of his/her needs.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
10
Moribund, fatal processes progressing 
rapidly.
0
Dead.
APPENDIX B 
Ultraviolet-Illuminated Operating Room Microscope 
Technical Aspects 
5-aminolevulinic acid (Gleolan® – a naturally occurring non-fluorescing metabolic precursor, 
induces synthesis of protoporphyrin IX (PPIX). PPIX fluoresces when exposed to the excitation 
light of blue-violet (wavelength 390-440nm.) It gives off a light with characteristic peaks 635 and 
704nm. This is best viewed by filtering (450 long pass filter) out most other wavelengths except a 
small amount of excitation light. 
Two special filters for the Gleolan® fluorescence are used in a standard operative microscope. 
The filters are a short pass (<440nm) filter which rotates in front of the microscope’s Xe light 
source. In addition, a special long pass (>440nm) barrier filter in the optical path allows clear 
viewing of the red fluorescence. Both filters are inserted and removed with one button on the 
microscope handle. With the push of that one button, the standard microscope can then go back 
to being the neurosurgical and spine microscope it was designed for. 
Using these modifications intraoperative detection of tumor fluorescence is possible without 
disturbing the routine of the surgical procedure. Switching between the two illumination modes 
does not require significant surgeon optical accommodation and does not interrupt the operation. 
All of these modifications are readily made to the standard neurosurgical microscope and 
requires no additional personnel in the operating room. 
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STUDY-20-00713
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32
The surgical operating microscope is a Class I exempt device that is commercially available in the 
United States. 
The surgical operating microscope will be adapted with a filter set intended to visualize 
fluorescence excitation in the wavelength range from 390nm to 440nm and for observation in the 
450nm range. The adaptation includes a combination of excitation and observation filters with 
slightly overlapping transmission integrated into their optical configuration. The proposed filter set 
is commercially available globally with the expectation of the United States, and is the appropriate 
filter set-up for intraoperative visualization of malignant gliomas after administration of Gleolan® 
• Leica OH4 with FL400 accessory
• Leica OH6 with FL400 accessory
• Zeiss Pentero with Blue 400 filter
Effective Date: 12/20/2024
End Date:12/19/2025

ICF_001.pdf: 
The Role of 5-Aminolevulinic Acid Fluorescence-Guided Surgery in Head and 
Neck Cancers: a Pilot Trial 
PI: Alfred-Marc Iloreta, MD
NCT05101798
Document Date: 12-20-2024


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 1 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)
__________________________
STUDY INFORMATION:
Study Title: The Role of 5-Aminolevulinic Acid Fluorescence-Guided Surgery in Head and Neck 
Cancers: a Pilot Trial
Study site(s): Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, Mount Sinai 
Union Square, New York Eye & Ear Infirmary of Mount Sinai.
Lead Researcher (Principal Investigator): Alfred-Marc Iloreta, Jr., MD
Physical Address: Mount Sinai Faculty Practice, Department of Otolaryngology - 234 E 85th Street, 
4th Floor, New York, NY 10028
New York Eye and Ear Infirmary of Mount Sinai - 310 E 14th Street, New York, NY 10003
Mount Sinai Union Square - 10 Union Square East, Suite 5B, New York, NY 10003
Mailing Address: One Gustave L. Levy Place Box 1189, NY, NY 10029 
Phone: (212) 241-9410
____________________________
SUMMARY OF THIS RESEARCH STUDY:
This document explains a research study you might be interested in joining.  Participation in the study 
is voluntary. You can agree to join or not. Your decision will not limit your ability to receive care at 
Mount Sinai. You should only agree to take part if you understand the study and if all of your 
questions about the research study are answered. If you do join the study, the research team must 
share any new information with you that may change your mind about taking part.
The purpose of this research study is to determine the diagnostic performance of 5-ALA and to assess 
if 5-ALA can be effectively used in FGS for different types of head and neck and skull base cancers.
 
Treatment for many head and neck cancers involves surgical resection, or removal, of the tumor. A 
potential complication of surgery is subtotal resection, in which some cancerous material fails to be 
removed. This is a problem because it can negatively impact patient survival and tumor regrowth after 
surgery. Because head and neck surgery involves aesthetically sensitive parts of the body and many 
complicated anatomical structures, it can be difficult for surgeons to ensure total tumor resection while 
minimizing the amount of healthy tissue they have to remove. Fluorescent-guided surgery (FGS) is a 
new method used to clearly visualize cancerous tissue during surgery in real-time. Before surgery, a 
medication that preferentially enters tumor cells is given to the patient. Tumor cells then glow brightly 
Effective Date: 12/20/2024
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when exposed to a particular kind of light during surgery, allowing the surgeon to distinguish between 
healthy and cancerous tissue. One such agent, 5-aminolevulinic acid (5-ALA), has been successfully 
used by neurosurgeons for FGS of different brain tumors. It is FDA approved and has been shown to 
be safer and more effective than other types of intraoperative imaging. However, while it shows 
promise, it has not yet been assessed for use in head and neck cancers.
If you choose to take part, you will be asked to: 

Attend a standard of care pre-operative visit with your physician where you will learn about the 
research study and determine if you are willing to participate

Sign and date this consent, to show your willingness and voluntary participation

On the day of your surgery, you will receive a single, oral dose of 5-ALA (20mg/kg) 8-12 hours 
prior to your surgery, which will cause the tumor to glow brightly during surgery. 

Your participation is expected to last 6 weeks. You will have your standard surgery to remove 
the head and neck tumor

All other procedures during your surgery and post-operative course will be performed as 
indicated for your head and neck tumor.

The study medication will be provided at no cost to subjects.

Agree to have your private information and study data samples stored for up to six years per 
Mount Sinai data retention policy.

Being in this research study will not lead to extra costs to you.

You will not be paid for participating in this research study. 
If you choose to take part, the main risks to you are the potential side effects of 5-ALA. Side effects of 
5-ALA administration are uncommon (>=1/1000, <1/100) and include transient nausea and occasional 
vomiting at 2.5 to 3 hours after receiving the drug, but the chances of these side effects occurring given 
the low dose used in our study (20mg/kg) are low. Other potential side effects are low blood pressure, 
your skin being hypersensitive to sunlight up to 24 hours after ingestion, and elevated liver enzyme 
levels. For 48 hours after your surgery, you will be in subdued light conditions to minimize the chance 
of any skin-related side effects from 5-ALA. We will also monitor your liver enzymes for 6 weeks after 
your surgery, and previous studies have shown that liver enzyme elevations have returned to normal in 
all patients after 6 weeks. Additional risks include all risks in patients normally undergoing surgery for 
head and neck tumor resection, regardless of participation in this research study. These risks include, 
but are not limited to, bleeding, infection, scarring, discomfort, complications of anesthesia, nerve injury, 
and other risks that your surgeon will discuss with you during your routine preoperative visits. Standard 
consent processes apply to all study subjects, as they are undergoing treatment for their disease. 
Subjects will be signing a separate clinical consent form, which details these risks in depth.
It is important to know that you may not get any benefit from taking part in this research. Others may 
not benefit either. However, possible benefits may be improved total surgical removal of the tumor while 
Effective Date: 12/20/2024
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AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
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minimizing the amount of healthy tissue removed for future patients. Increased total resection of the 
tumor can potentially decrease the risk of tumor regrowth after surgery. This method of visualizing the 
tumor during surgery may also be safer and more effective compared to current methods of 
intraoperative imaging. Others may benefit by the knowledge gained from this research study. 
You may choose not to participate without any penalty. Instead of participating in this research, you 
will receive all standard procedures regardless of whether you choose to take part in this research 
study.
If you are interested in learning more about this study, please continue to read below.
____________________________
STUDY PARTICIPATION: 
You may qualify to take part in this research study because you have been diagnosed with a new or 
recurrent head and neck or skull base tumor for which surgical resection is indicated and has been 
planned. 
Your participation in this research study is expected to last 6 weeks.
There are 23 people expected to take part in this research study across the Mount Sinai Health 
System.
Funds for conducting this research study are provided by the Icahn School of Medicine at Mount 
Sinai.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.
__________________________
DESCRIPTION OF WHAT IS INVOLVED:
If you agree to take part in this research study, here is what may be involved:
o
You will attend a standard of care pre-operative visit with your physician where you will learn 
about the research study and determine if you are willing to participate
o
If you are willing to participate, you will sign this informed consent form at the baseline visit
Effective Date: 12/20/2024
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AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
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o
At the baseline visit, standard pre-operative information will be collected including a medical 
history, physical exam, tumor imaging, blood tests and labs and a pregnancy test in women of 
child-bearing potential
o
On the day of your surgery, you will receive a single, oral dose of 5-ALA (20mg/kg) 8-12 hours 
prior to your surgery, which will cause the tumor to glow brightly during surgery.
o
You will have your standard surgery to remove the head and neck tumor. During the surgery, a 
standard surgical operating microscope will be used. In addition to the standard white light that 
is used in the operating room, a blue light will be switched on to visualize whether the tumor is 
fluorescent, allowing the surgeon to easily differentiate between healthy and cancerous tissue, 
and these images will be recorded. Only images will be saved; no tissue will be stored for 
research purposes.
o
All other procedures during your surgery and post-operative course will be performed as 
indicated for your head and neck tumor. You will undergo routine postoperative care in the 
hospital and outpatient clinic setting at 48 hours, 2 weeks and 6 weeks after surgery and you 
will also be monitored for adverse events throughout the course of your care. Data regarding 
your post-operative course will be recorded until 6 weeks after your surgery.
o
Because this research study involves the use of 5-aminolevulinic acid (5-ALA), a note must be 
included in your electronic medical record that you are taking part in the research. This way, 
anyone involved in your medical care will know that you are a study participant, and they can 
work to avoid any problems or negative outcomes that could arise if they do not know.
Pregnancy
If you can possibly get pregnant, a urine test for pregnancy will be done before you begin the study. 
Practicing effective birth control is important. No individual birth control is 100% effective. 
You cannot be included in the study if you are or become pregnant, as the study drug could harm your 
fetus. You also should not be in the study if you are producing milk to feed a child as the study drug 
could harm your baby.
Unless you are at least one year past menopause or have had a successful operation to make 
pregnancy impossible, you should use effective birth control. Unless you are sexually abstinent (not 
having genital sex) the recommended methods of birth control are:

The consistent use of approved hormonal birth control (pill, patches, or rings), 

An intrauterine device (IUD), 

Contraceptive injection (Depo-Provera), 

Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam), 

Sexual abstinence (no sexual activity), 

Sterilization (a vasectomy, getting tubes tied, or a hysterectomy).
Effective Date: 12/20/2024
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AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
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Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
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All birth control methods (other than abstinence and sterilization) are only effective if you use them 
properly, start them at least one month before you begin the research study, and continue using them 
throughout the research study and for one month after the research study ends. If you are unsure 
whether the method of birth control you use is approved to use while you are in this study, you should 
ask the Lead Researcher before you begin the study. If you are less than one-year post-menopausal, 
you could still become pregnant. If you or your partner becomes pregnant, or may be pregnant, at any 
time during the study or in the one month following the end of the study, you must tell a person from 
the research team immediately. The team may stop the study drug and refer you/your partner to an 
obstetrician/gynecologist for follow-up. 
Should you/your partner become pregnant, whether or not you/your partner have the baby, the people 
funding and overseeing the research may ask for information on the pregnancy, even if you are no 
longer part of the study. You/your partner will be asked for additional written consent to share this 
information if that happens.
 
Semen/Sperm:
Drugs can be found in semen and alter sperm. Since you are taking part in a study using experimental 
drugs or treatments, it is recommended that 1) you use a condom, 2) you do not get a partner 
pregnant or expose them to semen, and 3) you do not donate semen.  These recommendations apply 
both while you are taking the study drug, and for 3 months after you stop taking the study drug. You 
should refrain from impregnating a partner and/or donating sperm for a longer period of time than 90 
days after the study drug is administered.  This is because levels of the study drug may be present in 
the sperm and/or semen even after you stop taking the study drug.  You are encouraged to tell your 
partner(s) and/or their doctor(s) that you are participating in this clinical trial.
Effective Date: 12/20/2024
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CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
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Time and Events Table
____________________________
Study 
Assessment 
or Procedure
Baseline
(-60 to day 0 
before 
surgery)
Day 0 
(At 5-ALA 
administration)
Day 0 
(prior to 
surgery)
Within 
48h of 
surgery
Week 2
Week 6
Informed 
Consent
X
Demographics 
and Medical 
History
X
X
X
X
Physical 
Exam (vitals, 
weight, 
performance 
status)
X
X
X
X
X
Concurrent 
Medications
X
X
X
X
X
X
Adverse 
Events 
Evaluation
X
X
X
X
X
X
Tumor 
Imaging
X
Pregnancy 
testd
X
Other labs 
(CMP, CBC, 
GGT)a,b,c
X
X
X
X
5-ALAe
X
a. Albumin,  alkaline  phosphatase,  total  bilirubin,  bicarbonate,  BUN,  calcium,  chloride,  creatinine, glucose,   potassium,   
total   protein,   SCOT   (AST),   SCPT   (ALT),   sodium,   gamma   glutamyl transpeptidase (GGT)
b. Phosphorus, uric acid, creatinine kinase, and amylase will be added as clinically necessary/indicated.
c. Repeat only those labs that remain abnormal after 6 weeks unless attributed to other therapy
d. Pregnancy test (women of childbearing potential)- part of standard pre-operative protocol
e. 5-ALA is dosed as 20mg/kg. Oral administration is one-time only and based on actual weight on day of surgery.
Effective Date: 12/20/2024
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----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
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____________________________
USE OF YOUR DATA AND/OR SAMPLES:
The data and/or samples collected for this study will only be used to complete the study and not 
banked for future research. The research team will never use or share your personal information 
(such as, name, address, date of birth, social security number), study data and/or samples (blood, 
tissue, urine, saliva, or any other body matter) that are collected as part of this study for future 
research, even if your identity is removed. Your data and/or samples will only be used to complete this 
study and then they will be destroyed.
  ____________________________
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH:
If you decide to take part in this research study, you will be responsible for the following things:
You will be responsible for attending the appropriate postoperative follow-up care that is deemed 
necessary by your surgeon, calling the study team if you have any side effects, stopping the use of any 
medications that may interact with 5-ALA as instructed by your physician, using birth control methods 
as described in the Description of What’s Involved section and telling your physician immediately if you 
become pregnant.
____________________________
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION:
You will not be paid for taking part in this study. Being in this study will not cost you anything extra. 
Researchers will not pay you for your travel or the time it will take for you to be in the study. 
____________________________
POSSIBLE BENEFITS:
There is a chance this study may benefit you, but this is not guaranteed. Others may benefit from 
what researchers learn from the study. Possible benefits to you include improved total surgical 
removal of the tumor while minimizing the amount of healthy tissue for future patients. Increased total 
resection of the tumor can potentially decrease the risk of tumor regrowth after surgery. This method 
of visualizing the tumor during surgery may also be safer and more effective compared to current 
methods of intraoperative imaging. Others may benefit by the knowledge gained from this research 
study.
Effective Date: 12/20/2024
End Date:12/19/2025


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CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
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____________________________
POSSIBLE RISKS AND DISCOMFORTS:

Surgical risk: The therapeutic risks to the study subjects in the prospective cohort will include all 
risks in patients normally undergoing surgery for head and neck tumors. Standard consent 
processes apply to all study subjects, as they are undergoing treatment for their disease. Subjects 
will be signing a separate clinical consent form, which details these risks in depth.

Risk of loss of private information; this risk always exists, but there are procedures in place to 
minimize the risk.  

5-ALA side effects are uncommon (>=1/1000, <1/100) and include transient nausea and 
occasional vomiting which have been observed following oral administration of high doses of 5-
ALA. The incidence of nausea following 30 mg/kg and 60 mg/kg (oral) was 7 and 15%, 
respectively. No vomiting was observed with the lower dose, while 8% of the patients vomited 
following the higher dose.  In all instances, the nausea was mild and short -lived (less than15 min.) 
When vomiting occurred, it was mild and occurred only once in each patient. The nausea or 
vomiting occurred within 2.5 to 3 hours after receiving the drug. Furthermore, given our low study 
dose of 20 mg/kg, the chance of nausea or vomiting are very low.

Other potential side effects of 5-ALA are low blood pressure, your skin being hypersensitive to 
sunlight up to 24 hours after ingestion, and elevated liver enzyme levels. For 48 hours after your 
surgery, you will be in subdued light conditions to minimize the chance of any skin-related side 
effects from 5-ALA. We will also monitor your liver enzymes for 6 weeks after your surgery, and 
previous studies have shown that liver enzyme elevations have returned to normal in all patients 
after 6 weeks.

To further reduce the risk of any of these side effects of 5-ALA, your physician will be reviewing 
your concurrent medications and recommending that you stop any medications that may interact 
with 5-ALA. These include: use of other substances or medicines that cause a reaction to light 
(e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts) for 72h after 5-ALA 
administration. Patients should avoid exposure of eyes and skin to strong light sources (e.g. 
operating illumination, direct sunlight or brightly focused indoor light) for 24h after 5-ALA 
administration. Patients should not be exposed to any medicines or supplements that make the 
skin more sensitive to sunlight (e.g. sulfa antibiotics, st. John’s Wort, coal tar derivatives) up to 2 
weeks after 5-ALA administration. Within 24h after 5-ALA administration, other medicinal products 
that have potentially toxic effects to the liver should be avoided (antibiotics for tuberculosis such 
as isoniazid, certain antibiotics such as rifampin, St. John’s Wort, Kava root). In patients with pre-
existing cardiovascular disease, concomitant blood pressure medications should be used 
cautiously as 5-ALA has been shown to decrease overall blood pressure; your blood pressure will 
be monitored routinely as part of your regular treatment

There is a small risk that you will have a serious allergic reaction to 5-ALA, in which case you will 
immediately be removed from the study and you will be monitored until your side effects have 
resolved and you have returned to baseline.
Effective Date: 12/20/2024
End Date:12/19/2025


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
Risk of loss of private information; this risk always exists, but there are procedures in place to 
minimize the risk.

In addition to these risks, this research study may hurt you in ways that are not known. The 
unknown risks could be minor or major (death).

If you are pregnant or become pregnant, this research may hurt your baby or your pregnancy in 
ways that are unknown. The unknown risks could be minor or major (death) for the pregnancy. 
You should not become pregnant or get someone pregnant while you take part in this study. 
Please read the acceptable methods of birth control found under the Description of What Is 
Involved section of this document.
____________________________
OTHER OPTIONS TO CONSIDER:
You may decide not to take part in this research study. If you decide not to take part, this will not 
affect the clinical care you receive at Mount Sinai. The choice is totally up to you.
Instead of being in this research study, your choices may include; this includes your regular planned 
surgery without the use of 5-ALA.
____________________________
IN CASE OF INJURY DURING THIS RESEARCH STUDY 
If you are injured or made sick from taking part in this study, you will get medical care. Generally, it 
will be billed to you or your insurance. You will be responsible for all treatment costs not covered by 
your insurance, including deductibles, copayments, and coinsurance. This does not prevent you from 
seeking payment for injury related to malpractice or negligence. You can contact the Lead Researcher 
for more information.
____________________________
ENDING PARTICIPATION IN THE RESEARCH STUDY:
You may stop taking part in this study at any time.  No matter what you choose, your care and 
benefits through Mount Sinai will not be negatively impacted.
If you decide to stop being in the study, please contact the Lead Researcher or the research staff.   
You may also withdraw your permission for the researchers to use and share any of your protected 
information for research, but you must do so in writing to the Lead Researcher at the address on the 
first page. Even if you withdraw your permission, the Lead Researcher may still use the information 
Effective Date: 12/20/2024
End Date:12/19/2025


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 10 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)
that was already collected if that information is necessary to complete the research study. Your health 
information may still be used or shared after you withdraw your authorization if you have an adverse 
event (a bad effect) from taking part in the research study.
Withdrawal without your consent: The Lead Researcher, or Mount Sinai may stop your involvement in 
this research study at any time without your consent. This may be because the research study is 
being stopped, the instructions of the research team have not been followed, the Lead Researcher 
believes it is in your best interest, or for any other reason. If data and/or samples have been stored as 
part of the research study, they too can be destroyed without your consent. More possible reasons for 
removal from the study include if you become pregnant, if you are unable to comply with protocol 
requirements, if you demonstrate disease progression, if your physician judges that continuation of 
the study would not be in your best interest, if you develop a second malignancy (except for basal cell 
carcinoma or squamous cell carcinoma of the skin) that requires treatment, which would interfere with 
this study, if you are lost to follow-up, or if you exhibit a serious allergic reaction to 5-ALA 
administration. 
____________________________
CONTACT INFORMATION:
If you have any questions, concerns or complaints at any time about this research, or you think the 
research has harmed you, please contact the office of the research team and/or the Lead Researcher 
at phone number 212-241-9410.
If there is an emergency, please call 911 or go to the emergency room. Let the emergency room staff 
know you are in a research study so they can contact the Lead Researcher if needed.
____________________________
DISCLOSURE OF FINANCIAL INTERESTS:
Researchers sometimes get paid for consulting or doing work for companies that produce drugs, 
biologics or medical devices. If you have questions regarding industry relationships, you are 
encouraged to talk to the Lead Researcher or visit our website at http://icahn.mssm.edu/ where Mount 
Sinai publicly discloses the industry relationships of our faculty.   
____________________________
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION:
Effective Date: 12/20/2024
End Date:12/19/2025


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 11 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)
As part of this study, some of your private and/or protected health information will be obtained, used, 
and shared with your permission. There is a Federal Health Insurance Portability and Accountability 
Act (HIPAA) that makes sure this is done correctly and safely. 
What is protected health information (PHI)? 
PHI is the combination of two things:
1.
PHI contains information that identifies you. It will be used to contact you and link you to your 
health information, like name, date of birth, medical record number, and address.  
2.
PHI also contains health information, including information about your mental and physical 
health from your visits to doctors or hospitals, or from study visits. 
Every time you visit a hospital or your doctor, PHI is created and recorded in your medical record by 
your healthcare providers. In the same way, the PHI created as part of this study will be linked to who 
you are and your medical information. 
What PHI is collected and used in this research study, and might also be shared with others? 

Prior to Surgery: Past medical/surgical history, medications, vital signs (temperature, pulse, 
respirations, blood pressure), height, weight, Karnofsky performance score, complete Blood Count 
(CBC) to include white blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), hematocrit 
(HCT) , MCV, MCHC, WBC differential, platelet count, comprehensive metabolic panel (CMP) to 
include: albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes 
(sodium, potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin, pregnancy test 
(for females of child bearing potential), pre-operative imaging as part of standard operating 
procedure, gender, race/ethnicity.

On the day of surgery: physical exam, vital signs, adverse events, images captured during 
resection, pathology analysis (tumor classification, morphological factors, tumor markers, 
immunostaining, surgical margins).

Postoperatively, the following data will be collected (48h, 2 weeks and 6 weeks postoperatively): 
physical exam, vital signs, labs including albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SCOT (AST), 
SCPT (ALT), sodium, gamma glutamyl transpeptidase (GGT), concurrent medications, adverse 
events.
As part of this study, the research team at the hospital(s) involved in the research will collect your 
Date of Birth, MRN, First Name, Last Name, Date of Surgery, and Dates of Clinic Visits 
During the study, the researchers will gather information by: 

Reviewing and/or taking your medical history (includes current and past medications or 
therapies, illnesses, conditions or symptoms, family medical history, allergies, etc.) 
Effective Date: 12/20/2024
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THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 12 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)

Doing a physical examination that generally also includes blood pressure reading, heart rate, 
breathing rate, and temperature.

Completing the tests, procedures, questionnaires and interviews explained in the description 
section of this consent.
Why is your PHI being used?
Researchers need the information that identifies you so they can contact you during the study. They 
need your health information and the results of any tests and procedures being collected as part of 
this study to answer the questions posed in the study. The purpose of the study is discussed earlier in 
this consent form. Before researchers analyze the data, they remove any information that would let 
others know who you are or that you took part in the study. If researchers publish or present study 
results at scientific meetings, lectures, or other events, their presentations would not include any 
information that would let others know who you are, unless you give separate permission to do so.
The Lead Researcher may also use and share the results of these tests and procedures with other 
healthcare providers at Mount Sinai who are involved in your care or treatment. The research team 
and other authorized members of The Mount Sinai Health System (“Mount Sinai”) workforce may use 
and share your information to ensure that the research meets legal, institutional or accreditation 
requirements. For example:

The Mount Sinai Program for the Protection of Human Subjects is responsible for overseeing 
research on human participants and may need to see your information. 

If you receive any payments for taking part in this study, the Mount Sinai Finance Department 
may need your name, address, social security number, payment amount, and related 
information for tax reporting purposes.  

If the research team uncovers abuse, neglect, or reportable diseases, this information may be 
disclosed to appropriate authorities. 
Who, outside Mount Sinai, might receive your PHI?
As part of the study, the Lead Researcher, research team and others in the Mount Sinai workforce 
may disclose your PHI, including the results of the research study tests and procedures, to the 
following people or organizations: (It is possible that there may be changes to the list during this 
research study; you may request an up-to-date list at any time by contacting the Lead Researcher.)
-
The United States Department of Health and Human Services (DHHS) and the Office of 
Human Research Protection (OHRP) (the government organization that is responsible for 
protecting human research participants).
-
A Data Safety Monitoring Board or other committee that will monitor the study on an 
ongoing basis for safety.
-
The United States Food and Drug Administration.
In all disclosures outside of Mount Sinai, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier unless disclosure of the direct 
Effective Date: 12/20/2024
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THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 13 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)
identifier is required by law. Some records and information disclosed may be identified with a unique 
code number. The Lead Researcher will ensure that the key to the code will be kept in a locked file, or 
will be securely stored electronically. The code will not be used to link the information back to you 
without your permission, unless the law requires it, or rarely if the Institutional Review Board (IRB) 
allows it after determining that there would be minimal risk to your privacy. It is possible that a sponsor 
or their representatives, a data coordinating office, a contract research organization, may come to 
inspect your records. Even if those records are identifiable when inspected, the information leaving 
the institution will be stripped of direct identifiers.  Additionally, when applicable, the monitors, 
auditors, the IRB, OHRP, as well as the Food and Drug Administration (FDA) will be granted direct 
access to your medical records for verification of the research procedures and data. OHRP and FDA 
are authorized to remove information with identifiers if necessary to complete their task. By signing 
this document you are authorizing this access. The results of this research may be published. 
However, your name and other identifying information will be kept confidential.
For how long will Mount Sinai be able to use or disclose your PHI?  Your authorization for use of your 
PHI for this specific study does not expire.
Will you be able to access your records?
During your participation in this study, you will have access to your medical record and any study 
information that is part of that record. The research team is not required to release research 
information to you that is not part of your medical record.
Do you need to give the researchers permission to obtain, use or share your PHI?
NO! If you decide not to let the research team obtain, use or share your PHI, you should not sign this 
form, and you will not be allowed to volunteer in the research study. If you do not sign, it will not affect 
your treatment, payment, or enrollment in any health plans or affect your eligibility for benefits.
Can you change your mind?
If you decide to stop being in the study, please contact the Lead Researcher or the research staff.
The research team may ask you whether they can continue to collect information from your medical 
record. You will also have to decide if you wish to limit the continued use of the information collected 
during the study. Under US privacy laws you may also withdraw your permission for the researchers 
to use and share any of your protected information for research, but you must do so in writing to the 
Lead Researcher at the address on the first page. 
Even if you withdraw your permission, the Lead Researcher may still use the information that was 
already collected, but only to complete this research study. Your health information may still be used 
or shared after you withdraw your authorization if you have an adverse event (a bad effect) from 
taking part in the research study.
Effective Date: 12/20/2024
End Date:12/19/2025


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 14 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)
If you have not already received it, you will also be given The Hospital’s Notice of Privacy Practices 
that contains more information about how The Hospital uses and discloses your PHI.
It is important for you to understand that once information is disclosed to others outside Mount Sinai, 
the information may be re-disclosed and will no longer be covered by the federal privacy protection 
regulations. However, where possible, Mount Sinai has entered into agreements with those who will 
receive your information to continue to protect your confidentiality.
If researchers are reviewing your medical records or asking questions about your medical history or 
conditions, it is possible that they may learn information related to your HIV status. If that is the case, 
the following information concerns you. If researchers are not reviewing your medical records or 
asking questions about your medical history or conditions, then you may ignore the following section.
________________________________________________________________________________
Notice Concerning HIV-Related Information 
If you are authorizing the release of HIV-related information, you should be aware that the recipient(s) is 
(are) prohibited from re-disclosing any HIV-related information without your authorization unless permitted 
to do so under federal or state law. You also have a right to request a list of people who may receive or 
use your HIV-related information without authorization. If you experience discrimination because of the 
release or disclosure of HIV-related information, you may contact the New York State Division of Human 
Rights at (888) 392-3644 or the New York City Commission on Human Rights at (212) 416-0197. These 
agencies are responsible for protecting your rights.
_____________________________________________________________________________________
____________________________
How the Institutional Review Board (IRB) can help you:
This research has been reviewed and approved by an Institutional Review Board (IRB). You may 
reach a representative of the Mount Sinai Program for Protection of Human Subjects at telephone 
number (212) 824-8200 during regular work hours (Monday-Friday, 9am-5pm, excluding holidays) for 
any of the reasons listed below. This office will direct your call to the right person within the Mount 
Sinai Health System:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You are not comfortable talking to the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
Effective Date: 12/20/2024
End Date:12/19/2025


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Page 15 of 15
Study ID: STUDY-20-00713                   
Form Version Date: 18 Dec 2023
----------------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------------------
Rev 11.11.2022 (Amendment 1-03.09.2023)
ADULT PARTICIPANT:
Your signature below documents your permission to take part in this research study and to the use 
and disclosure of your protected health information. A signed and dated copy will be given to you.
_________________________
_________________________
__________
__________
Signature of Participant
Printed Name of Participant
Date
Time
PERSON EXPLAINING STUDY AND OBTAINING CONSENT:
_________________________
_________________________
__________
__________
Signature of Consent Delegate
Printed Name of Consent Delegate
Date
Time
WITNESS SECTION:
My signature below documents that the information in the consent document and any other written 
information was accurately explained to, and apparently understood by, the participant, and that 
consent was freely given by the participant.
_________________________
_________________________
__________
__________
Signature of Witness
Printed Name of Witness
Date
Time
Effective Date: 12/20/2024
End Date:12/19/2025