Clinical trial NCT03090412
Conditions: Stage I Oral Cavity Squamous Cell Carcinoma Stage II Oral Cavity Squamous Cell Carcinoma
Sponsor: Roswell Park Cancer Institute
Start date: 2018-03-07; Completion date: 2021-08-06
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II clinical trial studies how well photodynamic therapy with HPPH works compared to standard of care surgery in treating patients with oral cavity cancer. Photodynamic therapy can destroy or control disease by using a combination of drug, such as HPPH, and light and may be as effective as surgery in treating patients with oral cavity cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To test the non-inferiority of photodynamic therapy (PDT) to standard of care surgery by comparing the rate of tumor response after PDT to those observed after surgery, at 24 months post treatment.

SECONDARY OBJECTIVES:

I. To determine quality of life (QoL) at 6, 12, 18 and 24 months post PDT or surgery.

II. To assess the toxicity using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Version 4.0).

TERTIARY OBJECTIVES:

I. Immune markers (T cells). II. To investigate the correlation of the diffuse reflectance optical spectroscopy with tumor response to PDT.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo standard of care surgery on day 1.

ARM II: Patients receive HPPH intravenously (IV) over 1 hour on day 0 and undergo PDT on day 1.

After completion of study treatment, patients are followed up every 3-4 months in year 1 and every 3-6 months in year 2.

Arms: arm 1: Patients undergo standard of care surgery on day 1. arm 2: Patients receive HPPH IV over 1 hour on day 0 and undergo PDT on day 1.
Interventions: intervention 1: HPPH intervention 2: Laboratory Biomarker Analysis intervention 3: Photodynamic Therapy intervention 4: Quality-of-Life Assessment intervention 5: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Undergo PDT intervention 4: Ancillary studies intervention 5: Undergo standard of care surgery

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE: A Randomized Multicenter Phase II Study Using 2-1[Hexyloxyethyl]-2-
Devinylpyropheophorbide-A (HPPH) with PDT versus Standard of Care Surgery for 
Patients with T1/T2 N0 Squamous Cell Carcinoma of the Oral Cavity
Roswell Park Cancer Institute
Study Number:
I 33616                      NCT03090412
Initial Date:
15 July 2016
Amendment 1:
Amendment 2:
Amendment 3:
Amendment 4:
21 February 2017
5 June 2017
22 August 2019
14 January 2021
IND Holder:
Roswell Park Cancer Institute
Principal Investigator:
Jon Chan MD
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-3158
Jon.Chan@RoswellPark.org
Sponsor:
Roswell Park Cancer Institute
Industry Supporter:
Photolitec LLC
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party(ies) mentioned above. The use of such 
confidential information must be restricted to the recipient for the agreed purpose and must 
not be disclosed, published, or otherwise communicated to any unauthorized persons, for 
any reason, in any form whatsoever without the prior written consent of the party(ies) 
above.
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RPCI Study Contacts 
FOR NETWORK SITES: Please contact the RPCI Network Monitor for any study-related 
questions regarding sample handling, processing or shipping.
Study Personnel outside of RPCI-CRS who will be housing essential documents or 
receiving, analyzing or storing biological samples.
Name
Institution
Email
Role
Gal Shafirstein, DSc
Roswell Park Cancer 
Institute, Buffalo, NY
Gal.Shafirstein@RoswellPark.org
Treatment Planning
Sandra Gollnick, PhD
Roswell Park Cancer 
Institute, Buffalo, NY
Sandra.Gollnick@RoswellPark.org
David Bellnier, PhD
Roswell Park Cancer 
Institute, Buffalo, NY
David.Bellnier@RoswellPark.org
Drug uptake
Alan Hutson, PhD
Roswell Park Cancer 
Institute, Buffalo, NY
Alan.Hutson@RoswellPark.org
Statistical Analysis
Joseph D. 
Tario,Jr.PhD
Roswell Park Cancer 
Institute, Buffalo, NY
joseph.tario@RoswellPark.org
Flow Cytometry
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SYNOPSIS
Title / Phase
A Randomized Multicenter Phase II Study Using 2-1[Hexyloxyethyl]-2-
Devinylpyropheophorbide-A (HPPH) with PDT versus Standard of Care Surgery for 
Patients with T1/T2 N0 Squamous Cell Carcinoma of the Oral Cavity
Roswell Park Cancer 
Institute Study 
Number
I 33616
Roswell Park Cancer 
Institute Investigator
 Jon Chan, MD
Sponsor
Roswell Park Cancer Institute 
Industry Supporter
Photolitec LLC
Study Drug
HPPH (2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a)
Objectives
Primary:

To test the non-inferiority of PDT to standard of care surgery by comparing the 
rate of tumor response after PDT to those observed after surgery, at 24 months 
post treatment.
Secondary:

To determine quality of life (QoL) at 6, 12, 18, and 24 months post PDT or 
surgery.

To assess the toxicity using the CTEP NCI Common Terminology Criteria for 
Adverse Events (CTCAE Version 4.0).
Tertiary:

Immune markers (T cells).

To investigate the correlation of diffuse reflectance optical spectroscopy with 
tumor response to PDT (Appendix B).
Study Design

This is an open-label, randomized, multicenter Phase II study of HPPH-mediated 
PDT in patients with lesions that are diagnosed as previously untreated T1 N0 or 
T2 N0 SCC of the oral cavity. 114 participants will be randomized (1:1) to surgery 
(57) or PDT with HPPH (57). The randomization will be done at RPCI by the 
biostatistician.

Participants will be treated on an outpatient basis. Rarely, participants may require 
hospitalization, but this will be decided on a case by case basis. All participants 
will meet the inclusion and exclusion criteria.

Participants randomized to PDT with HPPH will be administered a single dose of 
HPPH at 4 mg/m2 via slow intravenous (IV) infusion over 1 hour. Approximately 
1 day later, the target tumor will be illuminated with a 665-nm laser light at dose 
of 140 Joules/cm2 delivered at a fluence rate of 150 mW/cm2. The participants 
will be scheduled to have clinical examination at 1 week, 4 - 6 weeks, 12-16 
weeks, and at 24 months post therapy. Pathological evaluation will be conducted 
by taking a 3-mm punch biopsy from the treated region during the 12-16 weeks 
clinical visit. In the event that a suspicious lesion is observed, the participants will 
be scheduled for a biopsy at the discretion of the treating physician. Participants 
will receive standard curative therapy 6 weeks after failing to respond to PDT with 
HPPH. Tumor response will be determined according to the revised response 
evaluation criteria in solid tumors (RECIST v1.1).
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Target Accrual and 
Study Duration
A maximum of 114 participants at 3 sites, including RPCI, will be enrolled. Accrual is 
expected to take up to 4 years. Each participant is expected to be on the study for two 
years and will be followed according to NCCN guidelines.
Study Procedures
Disease Evaluation: Baseline and as per the NCCN guidelines for T1/T2 SCC of the 
head and neck.
Quality of Life Questionnaire: Baseline, post treatment at 12 - 16 weeks and 6, 12, 
18, and 24 months.
Hematology: Baseline.
Chemistry: Baseline.
Performance Status: Baseline, post treatment at 12 - 16 weeks, and at follow-up 
visits.
Clinical Examination: Baseline and post treatment at 1 week, 4 - 6 weeks, 
12 - 16 weeks. We will follow the subjects according to the NCCN guidelines for 
patients with T1/T2 SCC, i.e. every 3 – 4 months (year 1), 3 – 6 months (year 2). 
Vital Signs: Baseline, Day 0, post treatment at 1 week, 4 - 6 weeks, 12 - 16 weeks, and 
at follow-up visits.
HPPH Infusion: Day 0
Blood Samples:  Day 0, 7, and 4-6 weeks  
Optical Spectroscopy:  Day 1 
Laser: Day 1
Adverse Events: From administration of study drug or surgery until 30 days after 
receiving study drug or surgery.
Statistical Analysis
The primary objective of this study is to test the non-inferiority of PDT to standard of 
care by comparing the rate of tumor response after PDT to those obtained after surgery.
This is a randomized multicenter Phase II trial with PDT with HPPH for the treatment 
of T1/T2 N0 primary tumors of the oral cavity. The design is based on a test for non-
inferiority of PDT compared to standard of care with regards to tumor response. 
Justification for use of a non-inferiority trial is that PDT may be viewed as a potential 
replacement for standard of care if it is established as less toxic than the standard of 
care yet still providing acceptable efficacy.
Sample Size Determination: The samples sizes of the trial are set at 57 in each of the 
standard of care and PDT groups. With the proposed sample sizes, there is 
approximately 80% power associated with the non-inferiority test when the true tumor 
response probabilities are equal to 85% in both groups.
Randomization: The randomization scheme will be generated at RPCI by the 
biostatistician. 114 participants will be randomized at a ratio of 1:1 to be treated with 
either standard of care surgery (57) or PDT with HPPH (57).
Efficacy Analysis: Objective tumor response will be tabulated overall. All participants 
who randomized to PDT treatment or surgery will be evaluable for response. Tumor 
response will be determined by comparing the photographs of the treated site (with 
reference ruler) before and after PDT or surgery.
Safety Analysis: The frequency of toxicities will be tabulated by grade across all 
cycles. All participants who randomized to HPPH PDT will be considered evaluable 
for toxicity.
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Participant Name (Network sites use participant initials):_______________________________
Medical Record No. (Network sites use participant ID):________________________________
Title: A Randomized Multicenter Phase II Study Using 2-1[Hexyloxyethyl]-2-
Devinylpyropheophorbide-A (HPPH) with PDT versus Standard of Care Surgery 
for Patients with T1/T2 N0 Squamous Cell Carcinoma of the Oral Cavity
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years of age.
2.
Have an ECOG Performance Status of ≤ 2. Refer to Appendix D.
3.
Participants with previously untreated T1/T2 N0 squamous cell carcinoma 
of the oral cavity with or without extension to the oropharynx.
4.
Histologically confirmed squamous cell carcinoma of the target tumor(s).
5.
Tumor thickness is 4 mm or less (measured clinically and/or by CT or 
MRI scan). 
6.
CT or MRI of the neck to confirm staging.
7.
Tumor accessible for unrestricted illumination for photodynamic therapy 
(PDT) (accessibility as determined by the physician).
8.
Life expectancy of at least 12 months in the judgment of the physician.
9.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while she is 
participating in this study, she should inform her treating physician 
immediately.
10. Participant or legal representative must understand the investigational nature 
of this study and sign an Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
Study participant meets all entry criteria:
Yes
No
Investigator Signature: ___________________________________
Date: ____________
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Participant Name (Network sites use participant initials):______________________________
Medical Record No.: (Network sites use participant ID):_______________________________
Title: A Randomized Multicenter Phase II Study Using 2-1[Hexyloxyethyl]-2-
Devinylpyropheophorbide-A (HPPH) with PDT versus Standard of Care Surgery 
for Patients with T1/T2 N0 Squamous Cell Carcinoma of the Oral Cavity
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “NO” or “N/A” for participant enrollment
Date
1.
Those who have had chemotherapy or radiotherapy or targeted agents within 
4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the 
study or those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier.
2.
Those with known brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events.
3.
Those with porphyria or with known hypersensitivity to porphyrins or 
porphyrin-like compounds.
4.
WBC < 4,000.
5.
Those with impaired renal and/or hepatic function, total serum 
bilirubin > 2 mg/dL, serum creatinine > 2 mg/dL, alkaline phosphatase 
(hepatic) or SGOT > 3 times the upper normal limit.
6.
Diagnostic biopsy reveals perineural invasion (PNI) and/or lymphovascular 
invasion (LVI).
7.
Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements.
8.
Nodal disease as detected by clinical exam or CT. 
9.
Pregnant or nursing females.
10. Unwilling or unable to follow protocol requirements.
11. Any condition which in the Investigator’s opinion deems the participant an 
unsuitable candidate to receive study drug.
12. Received an investigational agent within 30 days prior to enrollment.
13. Trismus or compromised airway.
14. Previous therapy to the target tumor site.
Study participant meets all entry criteria:
Yes
No
Investigator Signature: ___________________________________
Date: ____________
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TABLE OF CONTENTS
SYNOPSIS ......................................................................................................................................3
1
Background.....................................................................................................................12
1.1
Cancer of the Oral Cavity...............................................................................................12
1.2
Standard Treatment for Early Stage Cancer of the Oral Cavity .....................................12
1.3
Photodynamic Therapy for Early Stage Head and Neck Cancer....................................12
1.4
Preclinical Studies with HPPH .......................................................................................14
1.5
Clinical Studies: HPPH...................................................................................................14
1.5.1
Pharmacokinetics (PK) ...................................................................................................14
1.5.2
The HPPH Dose..............................................................................................................15
1.5.3
The Light Fluence Rate and Dose for Early Stage Head and Neck Cancer ...................15
1.6
Risks and/or Benefits......................................................................................................16
2
Rationale.........................................................................................................................16
2.1
Rationale for Ancillary Laboratory Studies....................................................................17
3
Objectives .......................................................................................................................17
3.1
Primary Objective...........................................................................................................17
3.2
Secondary Objectives .....................................................................................................17
3.3
Tertiary Objective...........................................................................................................18
4
Methodology...................................................................................................................18
4.1
Study Design...................................................................................................................18
4.1.1
Treatment Procedure.......................................................................................................19
4.1.2
Post Treatment Evaluation..............................................................................................20
4.2
Participant Quality of Life Evaluation............................................................................21
4.3
Management of the Neck and Salvage Surgery..............................................................21
4.4
Target Accrual and Study Duration................................................................................22
5
Participant Selection .......................................................................................................22
5.1
Inclusion Criteria ............................................................................................................22
5.2
Exclusion Criteria ...........................................................................................................23
5.3
Inclusion of Women and Minorities...............................................................................23
6
Investigational Products..................................................................................................23
6.1
Active Substance and Source..........................................................................................23
6.2
Drug Shipment................................................................................................................24
6.3
Storage, Preparation and Stability ..................................................................................24
6.4
Handling and Disposal....................................................................................................25
6.5
The Treatment Laser System..........................................................................................25
7
Treatment Plan for PDT with HPPH: .............................................................................25
7.1
Dosing and Administration.............................................................................................25
7.2
Participant Dose Modifications ......................................................................................25
7.3
Duration of Treatment ....................................................................................................25
7.4
Study Withdrawal ...........................................................................................................26
8
Study Procedures ............................................................................................................26
8.1
Participant Randomization and Registration ..................................................................27
8.2
Baseline Evaluations.......................................................................................................27
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8.3
Day 0 Infusion (Arm 2 – PDT with HPPH) ...................................................................27
8.4
Day 1 Treatment .............................................................................................................27
8.5
About 1 Week Post Treatment........................................................................................28
8.6
About 4 - 6 Weeks Post Treatment.................................................................................28
8.7
About 12 - 16 Weeks Post Treatment.............................................................................28
8.8
Post-Treatment Follow-Up Evaluations .........................................................................28
8.9
Schedule of Procedures and Observations......................................................................29
8.10
Correlative Studies Sample Collection and Processing..................................................33
8.10.1
Immune Monitoring for Isolation and Storage of Immune Cells ...................................33
8.10.2
Photosensitizer (HPPH) and Biomarker (Serum Alkaline DNase) Levels in Serum .....33
8.10.3
Diffuse reflectance optical spectroscopy........................................................................34
8.11
Pathology ........................................................................................................................35
8.12
Clinical............................................................................................................................35
9
Efficacy Evaluations.......................................................................................................35
9.1
Objective Tumor Response.............................................................................................35
9.2
Target Lesions ................................................................................................................35
9.3
Evaluation of Response ..................................................................................................36
10
Safety Evaluation............................................................................................................37
10.1
Adverse Events ...............................................................................................................37
10.1.1
Definition........................................................................................................................37
10.1.1.1 Diagnosis Versus Signs and Symptoms .........................................................................37
10.1.1.2 Adverse Events Occurring Secondary to Other Events..................................................37
10.1.1.3 Abnormal Laboratory Values .........................................................................................37
10.1.1.4 Preexisting Medical Conditions (Baseline Conditions)..................................................38
10.1.2
Grading and Relationship to Drug..................................................................................38
10.1.3
Reporting Routine Adverse Events ................................................................................39
10.2
Serious Adverse Events ..................................................................................................39
10.2.1
Definition........................................................................................................................39
10.2.2
Reporting Serious Adverse Events .................................................................................40
10.3
Investigator Reporting: Notifying Photolitec LLC.........................................................40
10.4
Follow-Up for Serious Adverse Events..........................................................................40
10.5
Unanticipated Problems..................................................................................................40
10.5.1
Definition........................................................................................................................40
10.5.2
Reporting Unanticipated Problems.................................................................................41
10.6
Safety Stopping Rule ......................................................................................................41
10.7
FDA Reporting ...............................................................................................................41
11
data and safety monitoring board ...................................................................................42
12
Statistical Methodology..................................................................................................42
12.1
Justification for the statistical design and the non-inferiority margin ............................43
12.2
Sample Size Determination ............................................................................................43
12.3
Efficacy Analysis............................................................................................................44
12.4
Adverse Event.................................................................................................................44
12.5
Interim Analysis and Criteria for Early Termination of the Study.................................45
13
Ethical and Regulatory Standards...................................................................................45
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13.1
Ethical Principles............................................................................................................45
13.2
Informed Consent ...........................................................................................................45
14
Study Responsibilities ....................................................................................................46
14.1
Data Collection ...............................................................................................................46
14.2
Maintenance of Study Documents..................................................................................46
15
Administrative Rules ......................................................................................................47
15.1
Revisions to the Protocol................................................................................................47
15.2
Termination of the Study................................................................................................47
15.3
Confidentiality ................................................................................................................47
16
Appendices .....................................................................................................................48
17
References.......................................................................................................................61
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IN-TEXT TABLES
Table 1.
Response to Therapy for SCC.....................................................................................16
Table 2
Schedule of Procedures and Observations for Participants Randomized to PDT.......30
Table 3
Schedule of Procedures and Observations for Participants Randomized to Surgery..32
Table 4
Time Point Response Criteria (+/- non-target disease) ...............................................36
Table 5
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies (Regardless of 
Expectedness) ................................................................................................................................39
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APPENDICES
Appendix A.
Instructions for Network Sites .............................................................................48
Appendix B.
Spectroscopy ........................................................................................................51
Appendix C
Chemical Sterilization..........................................................................................52
Appendix D
ECOG Performance Status...................................................................................53
Appendix E
Toxicity Serious Adverse Event Reports.............................................................54
Appendix F
Normal Tissue Toxicity Grading .........................................................................55
Appendix G.
Correlative Studies (if possible)...........................................................................56
Appendix H
Appendix H. University of Washington Quality of Life Questionnaire version 4 
(UW-QoLQ v4) .............................................................................................................................57
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1
BACKGROUND
1.1
CANCER OF THE ORAL CAVITY
Cancer of the head and neck is the sixth most prevalent cancer worldwide, with an incidence 
exceeding half a million cases annually.1 The most recent data from the NCI Surveillance, 
Epidemiology, and End Results (SEER) Program predicted that 48,330 men and women (34,780 
men and 13,550 women) would be diagnosed with and 9,750 men and women would die of cancer 
of the oral cavity and pharynx in 2016.2 These numbers represent an estimated 16.8% increase in 
the incident and 23.57% in death rate when compared to the published statistics in 2013 
(41,380 were diagnosed and 7,890 were expected to die from head and neck cancer).3 The steady 
increase in incidents and death rate suggest that there is an urgent need to improve the treatment 
for this specific cancer.  
1.2
STANDARD TREATMENT FOR EARLY STAGE CANCER OF THE ORAL 
CAVITY 
Surgery and radiotherapy are standard treatment modalities for T1/T2 oral cavity cancer (OCC).4 
Several studies demonstrated that surgery is the preferred treatment for oral squamous cell 
carcinoma (SCC), yielding superior 5-year survival rates when compared to radiation therapy.4,5 
Furthermore, the sequelae of radiation therapy such as xerostomia, chronic dental decay and risk 
of mandibular osteonecrosis remain long after the patient is “cured,” reducing the patients’ quality 
of life (QoL).6 
Effective surgical treatment of OCC requires wide local resection of the primary tumor with clear 
surgical margins. In order to secure tumor free margins the surgical procedures remove additional 
functional tissue often affecting speech and swallowing. Following the initial surgery, the risk 
of local recurrences is as high as 20%.7-9 Local recurrences are usually treated with further 
surgery, requiring more mucosal resection. Patients that have been cured with standard therapy 
also have a significant risk of developing second primary tumors, which has been associated with 
poor prognosis.10-12 Treatment of second primaries will increase patient morbidity. Currently, 
younger patients are being diagnosed with oral cancer, and their QoL is severely affected by 
standard of care therapies.6,13 It is important to provide this patient population with a first line 
therapy that will not cause irreversible long-term toxicities, and if failed, can be followed with 
standard surgery to improve the chance of cure.
Photodynamic therapy (PDT) can result in good local control of early stage OCC with minimal 
loss of tissue volume and excellent long-term healing that is expected to improve QoL.14-16 Our 
experience (including our collaborator, Dr. Biel) suggest that patients who failed to respond to 
PDT can be safely salvaged with standard surgery.17,18 
1.3
PHOTODYNAMIC THERAPY FOR EARLY STAGE HEAD AND NECK 
CANCER 
Numerous studies over the past 25 years have used photodynamic therapy (PDT) to treat early 
stage oral and oropharyngeal carcinomas.  While many of the early studies were single site with 
small numbers of patients, in 2004 a major prospective multi-center trial was conducted using 
mTHPC-PDT to treat early (carcinoma in situ, Cis -T2) disease.19 A total of 114 patients were 
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treated with an overall complete tumor response (CR) of 85% which was maintained in 85% of 
the patients for 1 year.  In 2010 Biel reported the cumulative results of treatment of Cis-T1 
carcinomas with Photofrin-PDT to be a CR of 94% with a 5 year response of 90%.20 A review of 
the literature showed that, between 1990 and 2013, 729 patients were treated with PDT with a 
cumulative overall tumor response rate of 0.85 (Table 1).  Importantly, healing was reported to be 
excellent and salvage treatment carried out by either surgery or repeated PDT resulted in 100% 
CR.20 Side effects were largely limited to photosensitivity and pain at the treatment site, which 
was easily managed by analgesics.  Photosensitivity was more pronounced and last longer when 
Photofrin was used; 20  however second generation photosensitizers, mTHPC and HPPH, resulted 
in only mild-moderate photosensitivity.21 Importantly, several studies have shown that PDT results 
in fewer treatment-associated morbidities that conventional therapies, including little to no nerve 
damage, minimal scarring and retention of organ function.18-22 The organ sparing nature of PDT 
has the potential to result in fewer complex reconstructive surgical interventions.  
Although no direct comparison studies showing superiority or at least non-inferiority to the 
standard of care (SoC) modalities of surgery or radiotherapy have been conducted, single site 
and retrospective studies have compared responses after PDT vs. surgery in early stage oral 
cancer. Karakullukcu et al. 23 found no significant difference in treatment outcome between PDT 
(n=55) and surgical removal (n=43) of T1s-T2 oral cancer.  A multicenter retrospective meta-
analysis of 126 PDT and 56 surgical T1 cases demonstrated a comparable CR and no significant 
differences in overall survival were observed between the two modalities.24
Thus, the breadth of experience in treatment of early stage oral cancer with PDT suggests that 
early oral malignancies are amenable to this non-invasive therapy and that the therapy can result 
in comparable outcomes to the SoC.  However, these findings need to be confirmed in a 
multicenter, randomized clinical trial.
  
Table 1. Clinical studies of PDT of early oral and oropharyngeal carcinomas.
Study
Year
n*
T
PS
CR
PR
NR
Ratio CR
Feyh et al. 
25,26
1990, 
1993
15
T1-T2
Photofrin
13
2
1.00
Grant et al. 27
1993
11
T1
Photofrin
10
1
0.91
Grant et al. 28
1993
4
T1
ALA
3
1
0.75
Fan et al. 29
1996
18
Cis-T1
ALA
14
3
1
0.78
Savary et al. 
30
1997
4
Cis-T1
mTHPC
4
1.00
Fan et al. 31
1997
20
Cis-T4
mTHPC
14
6
0.7
Schweitzer 32
2001
10
Cis-T2
Photofrin
8
2
0.8
Kϋbler et al. 
33
2001
25
T1-T2
mTHPC
22
3
0.88
Dilkes et al. 
34
2003
17
T1-T3
mTHPC
15
2
0.53
Copper et al. 
22
2003
29
T1-T2
mTHPC
25
4
0.83
Hopper et al. 
19
2004
114
Cis-T2
mTHPC
97
17
0.85
Biel 20  
2010
138
Cis-T1
Photofrin
131
9
0.94
Rigual et al. 
35
2009
20
Cis-T1
Photofrin
19
1
0.95
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Study
Year
n*
T
PS
CR
PR
NR
Ratio CR
Schweitzer 
and Somers36
2010
30
Cis-T2
mTHPC
24
6
0.8
Jerjes et al. 37
2011
38
T1-T2
mTHPC
22
10
6
0.58
de Visscher 
et al. 24
2013
156
T1-T2
mTHPC
127
29
0.81
Karakullukcu 
et al. 23
2013
55
T1-T2
mTHPC
49
6
0.89
Ikeda et al. 38
2013
25
Cis-T2
Photofrin
24
1
0.96
Rigual et al. 
18 
2013
17
T1-T2
HPPH
14
3
0.82
SUM
729
619
97
13
0.85
*n=number of patients; T=tumor size; PS=photosensitizer; CR=complete response; PR=partial response; 
NR=no response; mTHPC=m-tetrahydroxyphenylchlorin (Foscan®); HPPH-3-(1’-hexyloxyethyl) 
pyropheophorbide a.
While PDT with the FDA-approved drug porfimer sodium is a highly effective treatment modality, 
the persistence of porfimer sodium in skin and associated photosensitization necessitates complete 
protection from sunlight and other sources of bright light for periods up to 90 days. Further, 
porfimer sodium is activated by light at 630 nm, which is suboptimal for tissue penetration. These 
drawbacks have led to a search for other photosensitizers without these limitations.39
RPCI’s PDT center evaluated over 400 new photosensitizers as possible successors to Photofrin®. 
HPPH was identified in a preclinical quantitative structure-activity relationship study to be the 
most effective photosensitizer among a series of homologues with different numbers of methylene 
groups on the ether function.40
1.4
PRECLINICAL STUDIES WITH HPPH
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of HPPH 
can be found in the Investigator’s Brochure.
1.5
CLINICAL STUDIES: HPPH
1.5.1
PHARMACOKINETICS (PK) 
A detailed description of the PK studies, results and analysis, can be found in section 5.2 of the 
Investigator Brochure.   
One study in 25 cancer patients revealed estimated mean population α and β half-lives (95% 
confidence intervals) of 7.77 hours (3.46 - 17.6 hours) and 596 hours (120 - 2951 hours), 
respectively.41 No metabolites were detected in serum. A more extensive study of skin 
photosensitivity in 48 patients receiving HPPH doses of 2.5 - 6 mg/m2 and solar simulator light 
doses from 44.4 - 133.2 J/cm2 demonstrated that one day after drug administration the highest drug 
and light doses elicited a response of only erythema without edema. With over 70 patients treated 
to date we have found that (a) HPPH at doses of 2.5 - 6 mg/m2 has no systemic toxicity; (b) HPPH 
at doses of 3 mg/m2 and higher (to 6 mg/m2) approaches the effectiveness of Photofrin® (no head 
to head comparisons have yet been carried out), and (c) HPPH does not induce long-term cutaneous 
photosensitivity, based on in-house solar simulator testing and patient input.
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1.5.2
THE HPPH DOSE
In this protocol the participants will be treated with HPPH at fixed dose of 4 mg/m2. This dose is 
based on 5 studies, balancing safety and efficacy considerations, where HPPH-PDT was 
employed in the treatment of esophageal cancer - 2 studies in obstructing disease and 3 studies in 
high grade dysplasia, CIS and early adenocarcinoma.  The number of patients enrolled per HPPH 
dose was as follows: 11 at 6 mg/m2, 3 at 5 mg/m2, 36 at 4 mg/m2 and 32 at 3 mg/m2.  All were 
treated with 150 Joules/cm2.  The percentages of SAEs possibly, probably and definitely related 
to PDT were in order 46%, 33%, 28% and 28%, respectively.  Additionally, in the studies of 
high-grade dysplasia, CIS and early adenocarcinoma, 72% of complete responses were observed 
at 1 year at 3 and 4 mg/m2 combined, while no complete responses were observed at 5 or 6 
mg/m2.  There was no statistical difference in outcomes between 3 and 4 mg/m2 (Nava et al., 
Lasers in Surg. Med. 43, 705-12, 2011).42 The latter is likely due to photochemical oxygen 
depletion in tissue with high photosensitizer levels, which limits photodynamic action.
1.5.3
THE LIGHT FLUENCE RATE AND DOSE FOR EARLY STAGE HEAD AND 
NECK CANCER
Recently, RPCI has completed 3 Phase I studies of PDT with HPPH in the treatment of HNSCC. 
In the first study, (NCT00670397) PDT with HPPH was used intra-operatively in patients with 
resectable, primary or advanced recurrent SCC of the head and neck.43 This was a dose escalation 
study, where the drug dose was 4 mg/m2 and light dose was increased from 30 - 75 J/cm2. In this 
study, no serious adverse event was reported. The treatment was found to be safe at the maximum 
light dose of 75 J/cm2. Furthermore, major neurovascular structures and blood vessels were 
irradiated with the laser light during the PDT, but no carotid artery ruptures or cranial nerve injuries 
were observed, demonstrating that PDT with HPPH does not induce irreversible damage to healthy 
vital structures. This study also observed excellent healing of the overlaying skin in the 2 subjects 
that experienced skin burns as an adverse event. This healing was attributed to the fact that HPPH 
is not transported into fibroblasts.44 Thus, the native tissue that replaces the cancer cells regains its 
normal functions, significantly limiting function loss and minimizing scar formation.
In other Phase I studies, PDT with HPPH was used for dysplasia and T1 squamous cell carcinoma 
(SCC) of the oral cavity and oropharynx. Both trials, carried out at RPCI from April 2008 to 
June 2012, used HPPH at a fixed, previously determined dose of 4 mg/m2 administered 
systemically 20 – 28 hours before light delivery. In NCI-2010-02401 the light dose was escalated 
from 50 J/cm2 to 75 J/cm2, 100 J/cm2 and 125 J/cm2. In NCI-2010-01493 the light dose range was 
100, 125 and 140 J/cm2. Both trials had identical 3+3 designs, with an expanded cohort at 
140 J/cm2. Three courses of treatment were allowed for each oral lesion, with at least 6 weeks 
between treatments. Patients could have more than one lesion treated. The primary objectives were 
to establish the safety profile, to determine any dose-limiting toxicities (DLTs), and the maximum 
tolerated light dose (MTD). Secondary objectives were the determination of HPPH levels in blood 
and in the tumor tissue at the time of treatment, the extent of PDT-induced STAT3 crosslinking in 
the treated tissue, and the pathological treatment response as determined by biopsy at 3 months 
post treatment.
All patients who received PDT with HPPH reported the expected pain and edema at the treatment 
site, with pain lasting up to 4 weeks. Two patients in NCI-2010-02401 had Grade 3 edema at the 
application site at a light dose of 125 J/cm2, and one experienced respiratory distress shortly after 
illumination. This patient had presented with severe trismus from prior therapy, which 
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compromised precise light delivery and dosimetry to the lesion, which was located on the palate. 
The patient underwent a tracheostomy and recovered rapidly and completely without sequelae. 
This event, however, led to the closing of the protocol and addition of severe trismus as an 
exclusion criterion in NCI-2010-01493. Two patients in NCI-2010-01493 experienced Grade 3 
edema at the application site at 140 J/cm2, and one patient at that light dose experienced Grade 3 
ulceration. These adverse effects were temporary and resolved completely. Most patients chose a 
liquid or pureed diet due to pain for several days after treatment, but no medical intervention to 
support alimentation was needed. Mild sunburn reactions due to non-compliance with sun-
protection instructions were experienced in 1 patient in NCI-2010-02401 and 3 patients in 
NCI-2010-01493. An MTD was not reached at the highest planned dose level, but further 
escalation was forgone due to the danger of unacceptable swelling and ulceration.
The response to therapy for SCC is summarized in Table 1 below.
Table 1.
Response to Therapy for SCC
Light Dose, J/cm2
No. of SCC Lesions (Responses)
50
1 (1 CR)
75
2 (1 CR, 1 SD)
100
2 (1 CR, 1 unevaluable)
125
1 (1 CR)
140
17(14 CR*, 1 PR, 2 SD)
*Two lesions had complete disappearance of carcinoma but had minor remaining focal dysplasia. CR=complete 
response, PR=Partial response, SD=stable disease, as defined in Section 9.3 of this protocol.
The disease-free interval ranged from 5 to 40 months and follow-up is still ongoing. The CRs were 
also associated with increase in STAT3 crosslinking, which suggests that the responses were due 
to photodynamic reaction.45-47
The results of this study were recently published in Clinical Cancer Research (Rigual, Shafirstein 
et al. 2013).18
In this protocol the light fluence rate and dose will be fixed at 150 mW/cm2 and 140 J/cm2, 
respectively. 
1.6
RISKS AND/OR BENEFITS
For participants that will have partial or complete response to PDT, the potential benefits include 
complete clinical regression of the tumor. Participants that do not respond to PDT may not benefit 
from this treatment. There is no guarantee of the outcome nor is it possible to predict whether or 
not the participant will respond to HPPH mediated PDT.
This is a Greater Than Minimal Risk study according to IRB criteria. The most likely potential 
risks associated with the PDT are short term edema and pain.
2
RATIONALE
Surgical resection and radiotherapy are front line therapies for T1 and T2 oral cavity cancer. 
However, these therapies are associated with multiple morbidities and impaired QoL issues such 
as alteration of speech, dysphagia and xerostomia. PDT, which involves the activation by light of 
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a tumor-localized photosensitizer, has proven to be an effective local treatment for a range of solid 
tumors. It has the potential to become an effective first line treatment modality for this disease for 
the following reasons: it is minimally invasive, has low toxicity, is not associated with any long-
term morbidity and is repeatable. Importantly, it allows the physician to reserve conventional, 
more toxic treatments such as radiotherapy and chemotherapy for later application, if needed.
The purpose of this multicenter study is to test the non-inferiority of PDT with HPPH to standard 
of care by comparing the rate of tumor response and QoL after PDT to those obtained after surgery 
in participants with previously untreated T1/T2 N0 SCC of the oral cavity.
Phase I studies have demonstrated that this treatment is safe. These studies also determined the 
safe drug and light dosages: 4 mg/m2 and 100 - 140 J/cm2, respectively. Data also suggest that 
early stage SCC may have excellent response to this therapy (see Table 1).
In our recent study with HPPH-PDT, all the patients with T1/T2 who failed to have CR to PDT 
were successfully salvaged with surgery.18 Importantly, in patients with invasive disease who 
achieved only PR, the disease could be downgraded to dysplasia, thus minimizing salvage surgery.  
While all studies with HPPH-PDT to date have been Phase I studies, the response to PDT is swift 
and all patients, with few exceptions, have been assessed for response by pathological analysis.
We believe that PDT with HPPH is a viable option to treat patients with T1/T2, because:

HPPH-PDT is expected to be an organ sparing treatment option, and failures can be 
salvaged with surgery.  

HPPH, at clinically effective antitumor doses, is associated with significantly reduced 
cutaneous photosensitivity that rapidly declines over several days.41

The CR to HPPH-PDT is expected to be 85%, which would be comparable to cure rates 
after the initial surgery that is associated with 20% local recurrence. 7-9 

Noninvasive optical spectroscopy has potential to serve as a surrogate reporter for tumor 
response to HPPH-PDT.48
Therefore, we hypothesize that patients may choose a treatment option, such as PDT with HPPH, 
if it provides non-inferior cure rate at the time of the initial treatment.  
2.1
RATIONALE FOR ANCILLARY LABORATORY STUDIES
In the current study, immune cells will be collected from participants before and after PDT and 
tested for reactivity to the participant’s tumor cells. These will only be collected from participants 
randomized to PDT with HPPH. Refer to Appendix G.
3
OBJECTIVES
3.1
PRIMARY OBJECTIVE

To test the non-inferiority of PDT to standard of care surgery by comparing the rate of tumor 
response after PDT to those observed after surgery, at 24 months post treatment. 
3.2
SECONDARY OBJECTIVES

To determine quality of life (QoL) at 6, 12, 18, and 24 months post PDT or surgery. 

To assess the toxicity using the CTEP NCI Common Terminology Criteria for Adverse 
Events (CTCAE Version 4.0).
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3.3
TERTIARY OBJECTIVE

Immune markers (T cells).

To investigate the correlation of the diffuse reflectance optical spectroscopy with tumor 
response to PDT (Appendix B).
4
METHODOLOGY
4.1
STUDY DESIGN
This is an open-label, randomized, multicenter Phase II study of HPPH-mediated PDT in 
participants with lesions that are diagnosed as previously untreated T1 N0 or T2 N0 SCC of the 
oral cavity. Participants will be randomized at a ratio of 1:1, to be treated with either surgery (57 
participants) or PDT with HPPH (57 participants). The randomization will be done at RPCI by the 
biostatistician. The study schema is depicted in Figure 1.
Participants will be treated on an outpatient basis. Rarely, those undergoing HPPH with PDT may 
require hospitalization but this will be decided on a case by case basis. Participants undergoing 
surgery may be hospitalized.
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4.1.1
Treatment Procedure
Figure 1.
Study Schema
Consent, Diagnosis and Staging
Baseline Pathology and QoL
Day -1 to -45
RANDOMIZATION
1:1
Arm 1
Standard of Care Surgery
Arm 2
PDT with HPPH
Adverse Events 
Day 0 (HPPH), Week 1 and 30 
days
Response and QoL
12-16 Weeks Post Therapy
QoL
6, 12, 18, and 24 Months
Tumor Response at
2 Years Post Therapy
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For those participants randomized to HPPH with PDT, a single dose of HPPH at 4 mg/m2 will be 
administered via slow intravenous (IV) infusion over 1 hour. Approximately 24 hours 
(± 4 hours) later, the target tumor will be illuminated with a 665 ± 3 nm laser (ML7710-665 
LASER, Modulight, Inc., Tampere, Finland).  A total light dose of 140 J/cm2 at a fluence rate of 
150 mW/cm2 will be delivered with a single quartz fiber optic equipped with a micro lens 
(Frontal Light Distributor Model FD1, Medlight SA, Switzerland). In areas that preclude direct 
illumination of the lesion and margins with a microlens fiber, the light will be delivered through 
a cylindrical diffuser fiber with a diffuser end (Medlight SA, Switzerland) that will be inserted 
into a 10 mm in diameter flexible applicator (Frieburg Flap, Elekta Inc. Atlanta, GA).  The 
Frieburg Flap is an FDA approved device designed to keep radiation source at constant distance 
from the treatment surface (see attached letter of approval). Multiple cylindrical fibers (in 
parallel) can be inserted into the flap to cover an entire tumor and margins in curved surfaces.  
The light through each cylindrical diffuser will be delivered at a fluence rate of 495 mW/cm 
(accounting for about 5% loss) to a total light dose of 462 J/cm, which is equivalent to surface 
illumination of 150 mW/cm2 and 140 J/cm2.  The PDT center at RPCI will provide sections of 
the Frieburg Flap that will need to be sterilize prior to use, following the manufacturer 
instructions (see attcahed).  The entire tumor and 5 mm - 10 mm margins will be illuminated. 
The remainder of the oral cavity will be shielded to avoid illumination of healthy tissue.
4.1.2
Post Treatment Evaluation
Participants will be scheduled to have a clinical examination at 1 week and within 4 - 6 weeks and 
at 12 – 16 weeks post therapy. In the event that a suspicious lesion is observed, participants will 
be scheduled for a biopsy at the discretion of the treating physician, at 4-6 weeks post treatment. 
In addition, a scheduled pathological evaluation will be conducted by taking a 3-mm punch biopsy 
from the treated tumor site during the clinical visit at 12-16 weeks post therapy.
Tumor response will be determined at 24 months post treatment. The treating physician will 
examine the clinical response and a photograph of the treatment site will be taken with paper ruler, 
to determine the reduction in the lesion size, according to RECIST v1.1. A biopsy may be taken, 
if clinically indicated. The biopsies will be processed following the standard of care pathology. A 
clinical pathologist will examine the processed tissue section and determine the pathological 
response.
Participants who have partial or no-response will be offered standard therapy, at the discretion of 
the treating physician.
We hypothesize that non-responders or partial responders in the PDT arm are likely to be 
participants whose tumor does not retain HPPH. For this subset of participants that are treated with 
PDT at RPCI, an additional biopsy (50 mg tissue mass) will be taken at the time of excision of the 
recurred tumor to evaluate cellular mechanisms that contribute to tumor retention of HPPH. The 
biopsy sample is immediately dropped into a sterile 15-ml screw-cap tissue culture tube containing 
5 ml of serum-free RPMI medium. A set of such tubes are prepared prior to surgery and can be 
stored at 4°C for up to a month until use. A research nurse (or other personnel in the operating 
room, OR) will label the sample tube with an identifier code pertaining to the case, but without 
inclusion of any PHI. The tube containing the biopsy sample will be placed either into a 
refrigerator or bucket of ice until pick-up by a member of the investigating laboratories (Drs. 
Shafirstein or Baumann, as detailed below). The OR personnel will inform the research associate 
in the laboratories of either Dr. Shafirstein or Dr. Baumann via telephone or text message. The 
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associate will pick-up the sample tube at the entrance to the OR and immediately carry it to the 
laboratory of Dr. Baumann, or Dr. Shafirstein. 
The analysis will be performed in vitro by generating primary tumor cell culture from the biopsy 
material. The tumor cells will be incubated with HPPH and uptake and retention monitored over 
72 hours in the live cultures by microscopic imaging. HPPH fluorescence will serve as indicator 
for subcellular location and concentration of HPPH.
Contact person in Dr. Baumann laboratory:
Erin Tracy
Research Associate
Department of Molecular and Cellular 
Biology
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716  8458175 (Office), 
Cell: (716) 408-7206
Contact person in Dr. Shafirstein laboratory:
Michael Habitzruther
Research Technologist
Photodynamic Therapy Center
Department of Cell Stress Biology
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716 845 3551 (Office)
Cell: (716) 809-0365
4.2
PARTICIPANT QUALITY OF LIFE EVALUATION
Participants’ QoL will be evaluated with the widely accepted University of Washington Quality 
of Life Questionnaire Version 4 (UW-QoLQ v4).49,50 It has been tested in several prospective 
studies and found to be reproducible, reliable, and valid for head and neck cancer patients.51 It is 
simple to complete, employs a simple algorithm to compute the overall score, and is easy to 
interpret while yielding objective results.51 This version includes 12 individual Likert-scale items 
and 4 global questions. Each participant’s overall score on the UW-QoLQ v4 will be calculated at 
baseline, at 12-16 weeks, and at 6, 12, 18, and 24 months post-PDT.
4.3
 MANAGEMENT OF THE NECK AND SALVAGE SURGERY 
The management of the neck will be according to standard of care, at the discretion of the treating 
surgeon. If the participant, based on the pathology of the neck dissection or primary oral cancer 
resection, has perineural invasion, extracapsular spread, or requires additional therapies including 
radiation or chemotherapy, they will be dropped from the study and replaced with another 
participant.
Participants will receive standard curative therapy 6 weeks after failing to respond to PDT with 
HPPH. All the participants who will have disease progression, local recurrence, or partial or no 
response (PR, NR) following the PDT with HPPH will be considered treatment failures. The 
determination will be performed during the study visits, and based on clinical exam and 
pathology, if clinical exam is unclear.
The surgeon will provide a surgical plan for every patient, including those randomized to PDT.  If 
the patient requires salvage surgery post-PDT, the surgeon will compare the salvage surgery 
specimen diameter to the diameter of the spot size used for PDT.  This data will be used to 
demonstrate whether PDT affects the surgical plan. 
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4.4
TARGET ACCRUAL AND STUDY DURATION
A maximum of 114 participants at 3 sites, including RPCI, will be enrolled. Accrual is expected 
to take up to 4 years. Each participant is expected to be on the study for two years and will be 
followed according to NCCN guidelines.
5
PARTICIPANT SELECTION
The treating physician or his designee at each network site will determine eligibility.
5.1
INCLUSION CRITERIA
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years of age.
2. Have an ECOG Performance Status of ≤ 2. Refer to Appendix D.
3. Participants with previously untreated T1/T2 N0 squamous cell carcinoma of the oral 
cavity with or without extension to the oropharynx.
4. Histologically confirmed squamous cell carcinoma of the target tumor(s).
5. Tumor thickness is 4 mm or less (measured clinically and/or by CT or MRI scan). 
6. CT or MRI of the neck to confirm staging.
7. Tumor accessible for unrestricted illumination for photodynamic Therapy (PDT) 
(accessibility as determined by the physician).
8. Life expectancy of at least 12 months in the judgment of the physician.
9. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she is participating in this study, she should inform her treating physician 
immediately.
10. Participant or legal representative must understand the investigational nature of this study 
and sign an Institutional Review Board approved written informed consent form prior to 
receiving any study related procedure.
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5.2
EXCLUSION CRITERIA
Participants will be excluded from this study for the following:
1. Those who have had chemotherapy or radiotherapy or targeted agents within 4 weeks 
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have 
not recovered from adverse events due to agents administered more than 4 weeks earlier.
2. Those with known brain metastases should be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events.
3. Those with porphyria or with known hypersensitivity to porphyrins or porphyrin-like 
compounds.
4. WBC < 4,000.
5. Those with impaired renal and/or hepatic function (total serum bilirubin >2 mg/dL, serum 
creatinine > 2 mg/dL, alkaline phosphatase (hepatic) or SGOT > 3 times the upper normal 
limit.
6. Diagnostic biopsy reveals perineural invasion (PNI) and/or lymphovascular invasion 
(LVI).
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
8. Nodal disease as detected by clinical exam or CT.
9. Pregnant or nursing females.
10. Unwilling or unable to follow protocol requirements.
11. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
12. Received an investigational agent within 30 days prior to enrollment.
13. Trismus or compromised airway.
14. Previous treatment in the target tumor area.
5.3
INCLUSION OF WOMEN AND MINORITIES
Both men and women and members of all races and ethnic groups are eligible for this study.
For Network Sites, refer to Appendix A for site specific instructions.
6
INVESTIGATIONAL PRODUCTS
6.1
ACTIVE SUBSTANCE AND SOURCE
The drug (photosensitizer) to be used in this study is 2-[1-hexyloxyethyl]-2-Devinyl 
pyropheophorbide-a (HPPH).
The HPPH is formulated for injection as follows:
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Raw Materials for HPPH Formulation
Raw Material Name
Manufacturer Name/ Part Number
Supplier Name/Part Number
Quantity in 2000 gram 
Batch
HPPH
Syngene/S14/FP/15/00053
2.40 gm
Sterile Water for Injection, USP
VWR/B. Braun Medical/L8501-01
1862.81 gm
190 Proof Ethanol*, USP
VWR/Spectrum/ET108-1LTGL
34.36 gm
Dextrose, Anhydrous, USP multi-
compendial
VWR/JT Baker/JT1920-5
98.04 gm
Sodium Carbonate, NF
VWR/Spectrum/95035-752
0.26 gm
Tween 80*, USP
VWR/JT Baker/JT4117-4
2.13 gm
Total
2000.00 gm
pH adjustment after formulation
Phosphoric Acid, NF, FCC
VWR/JT Baker/JT0262-1
0.082 gm
Sterile Water for Injection, USP
VWR/B. Braun Medical/L8501-01
8.12 gm
*Ethanol and Tween 80 percentages are volume/volume.
The concentration of HPPH vials will be 1.13 mg/mL.  
6.2
DRUG SHIPMENT
The HPPH will be provided by Photolitec (Photolitec, LLC. Buffalo, NY) and shipped frozen, on 
dry ice to the participating sites.
Each receiving site will document the date of receipt of the shipment. Drug shipment records will 
be retained by the investigational pharmacist or designee.
6.3
STORAGE, PREPARATION AND STABILITY
Stability:  The current drug has been found to be stable for up to 6 months. Long-term stability 
studies will be ongoing during the course of this study.
Storage and Preparation:  HPPH vials will be stored frozen (a standard -20 C freezer), thawed 
at room temperature prior to administration, dispensed by the pharmacy of participating sites and 
administered within 4 hours of being removed from the freezer. The final dose should be protected 
from light.  
Documentation:  A careful record of each vial dispensed (including lot number) will be 
maintained. This record will also include the date of drug administration and the participant ID for 
whom the drug was made available.
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6.4
HANDLING AND DISPOSAL
The manufacturer (Photolitic) will send the investigational drug to the RPCI research pharmacy 
and participating sites. Study drugs must be handled as cytotoxic agents and appropriate 
precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record may be 
reviewed by the Sponsor’s staff or representative. It is the Investigator’s responsibility to ensure 
that an accurate record of investigational drug issued and returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices at the site after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
6.5
THE TREATMENT LASER SYSTEM 
In this study we will use a Modulight laser (ML7710-665). This is a medical laser designed for 
PDT. This laser system can deliver the light fluence rate (W/cm2) and dose (J/cm2) at the 
wavelength (665 ± 3 nm) required to activate the HPPH. The laser system includes a calibration 
port, and a SanDisk memory card for storing device history data. The PDT center at RPCI 
purchased this laser model for research evaluation. 
The participating sites will use the same laser model and identical treatment fibers.
7
TREATMENT PLAN FOR PDT WITH HPPH:
7.1
DOSING AND ADMINISTRATION
For participants randomized to HPPH with PDT, the light and drug dose will be fixed, 150 
mW/cm2 to deliver 140 J/cm2 of 665-nm light and 4 mg/m2 drug, respectively. The HPPH product 
will be added to 100 cc intra venous (i.v.) bag of D5W and infused via i.v. pump over 1 hr.
The justifications for selecting these doses are provided in sections 1.4.1 and 1.5.1. Treatment will 
be administered in an outpatient basis in most cases. Reported adverse events (AEs) and potential 
risks are described in Section 10.1.
7.2
PARTICIPANT DOSE MODIFICATIONS
The drug dose and light dose will not be modified.
7.3
DURATION OF TREATMENT
Participants may remain on study in the absence of disease progression, unacceptable toxicity or 
withdrawal from study.
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7.4
STUDY WITHDRAWAL
Upon participant withdrawal from the study, all end of study evaluations and tests will be 
conducted. All participants who discontinue due to an AE must be followed until the event resolves 
or stabilizes. Appropriate medical care should be provided until signs and symptoms have abated, 
stabilized, or until abnormal laboratory findings have returned to acceptable or pre-study limits. 
The final status of the AE will be reported in the participant’s medical records and the appropriate 
eCRF.
Reasons for study withdrawal should be classified as follows:

Death.

Progressive disease.

Treatment-related toxicity.

Toxicity unrelated to treatment.

Investigator judgment.

The Investigator may withdraw a participant if, in his/her judgment, it is in the participant’s 
best interest to do so.

Participant receives an additional adjuvant therapy.

Noncompliance

Participant voluntary withdrawal

A participant may withdraw from the study at any time, for any reason. If a participant 
discontinues treatment, an attempt should be made to obtain information regarding the 
reason for withdrawal.

Participants in which the surgical pathology demonstrates perineural invasion, 
extracapsular spread or the participant requires additional therapy including radiation or 
chemotherapy.
Participants who are unavailable for follow-up evaluations should be classified as lost to follow-
up for 1 of the following reasons:

Lost to follow-up: For a participant to be considered lost to follow-up, the investigator must 
make two attempts to re-establish contact with the participant. The attempts to re-establish 
participant contact must be documented (e.g., certified letter).

Death: Date and cause of death will be recorded for those participants who die within 
30 days after last dose of study drug (telephone contact with family is acceptable).
8
STUDY PROCEDURES
Unless otherwise defined in the written protocol text, all procedures/assessments will be conducted 
in accordance with RPCI Clinical Research Services Standard Operating Procedures.
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8.1
PARTICIPANT RANDOMIZATION AND REGISTRATION
We will employ a web-based stratified blocked randomization scheme developed at RPCI by the 
biostatistician in conjunction with the GOG Foundation Statistical & Data Management Center. 
Participants will be randomized stratified by study site with permuted blocks of size 4 within strata 
and will assigned to standard of care surgery or PDT with HPPH. Study sites will need to have 
IRB approval entered into the system prior to accessing the randomization system. Eligibility of 
each participant will be established prior to randomization.
Informed consent MUST be completed prior to receiving any study related procedures.
8.2
BASELINE EVALUATIONS
The following will be performed within 1 to 45 days prior to administration of study drug or 
surgery:

History, physical

Clinical examination with photograph of lesion if possible.

Confirm tumor staging with CT or MRI scans of the head and neck and chest. 

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, body weight, and 
height)

Hematology [(i.e., complete blood count (CBC) with automated differential]: WBC, RBC, 
HGB, HCT, platelet, MCV, MCH, MCHC, % neutrophils, absolute neutrophils, % 
monocytes, absolute monocytes, % eosinophils, absolute eosinophils, % basophils, 
absolute basophils, % lymphocyte, absolute lymphocyte, platelet confirmation (as 
clinically indicated), and differential confirmation (as clinically indicated)

Chemistry (i.e., complete metabolic panel (CMP): chloride, CO2, potassium, sodium, 
BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap)

Biopsy (diagnosis)

HCG urine or serum for women of childbearing potential

Performance status (ECOG): Appendix D

Evaluate lesion size

Quality of Life Questionnaire: Appendix H
8.3
DAY 0 INFUSION (ARM 2 – PDT WITH HPPH)

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, and body weight)

Correlative studies blood samples

HPPH infusion

Adverse events
8.4
DAY 1 TREATMENT

Laser PDT with HPPH (Arm 2) or Surgery (Arm 1)

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, and body weight)

Optical spectroscopy (Arm 2)
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
Normal tissue toxicity grade (Arm 2, Appendix F)
8.5
ABOUT 1 WEEK POST TREATMENT

Clinical examination with photograph of lesion if possible

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, and body weight)

Correlative studies blood samples (for participants randomized to PDT only)

Normal tissue toxicity grade (Appendix F)

Adverse events
8.6
ABOUT 4 - 6 WEEKS POST TREATMENT

Clinical examination with photograph of lesion if possible

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, and body weight)

Correlative studies blood samples (for participants randomized to PDT only)

Normal tissue toxicity grade (for participants randomized to PDT only) (Appendix F)

Adverse events 
8.7
ABOUT 12 - 16 WEEKS POST TREATMENT

Clinical examination with photograph of lesion if possible

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, and body weight)

Performance status (ECOG): Appendix D

Response, clinical (for both arms)

Response, pathological, biopsy for all participants.

Quality of Life Questionnaire: Appendix H
8.8
POST-TREATMENT FOLLOW-UP EVALUATIONS
Post treatment follow-up evaluations will occur every 3 - 4 months in year 1, 3 - 6 months in 
year 2, per the NCCN guidelines.

Clinical examination with photograph of lesion, if possible

Vital signs (i.e., temperature, heart rate, respiratory rate, blood pressure, and body weight)

Performance status (ECOG): Appendix D

Response, clinical (at each follow-up and at 2 years)

Response, pathological, biopsy, will be performed during routine visits, only if clinically 
indicated

Confirm tumor staging with CT or MRI scans of the head and neck and chest, only if 
clinically indicated

Quality of Life Questionnaire at 6, 12, 18, and 24 months: Appendix H.
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8.9
SCHEDULE OF PROCEDURES AND OBSERVATIONS
The schedule of procedures and observations for this study is summarized in Table 2 and Table 3 
below.
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Table 2
Schedule of Procedures and Observations for Participants Randomized to PDT
Baseline1
Day 0
Infusion
Day 1
Treatment
~1 Week 
Post 
Treatment
~4-6 Weeks 
Post Treatment
~12-16 Weeks 
Post Treatment
Follow-Up2
History, Physical
X
Clinical Exam (with lesion photograph 
if possible)
X
X
X
X
X
Confirm tumor staging with CT or 
MRI scans of the head and neck and 
chest
X
X10
Vital Signs (i.e., temperature, heart 
rate, respiratory rate, blood pressure, 
body weight, and height)3
X
X
X
X
X
X
X
Hematology5
X
Chemistry6
X
Blood Samples (if possible) for 
correlative studies (immune, 
photosensitizer & biomarker analyses 7
X
X
X
Biopsy (diagnosis)
X
HCG urine or serum for women of 
childbearing potential
X
HPPH Infusion
X
Optical spectroscopy 
X
Laser
X
Normal Tissue Toxicity Grade
X
X
X
Performance Status/ECOG 
X
X
X
Response, Clinical 
(Evaluate Lesion Size)
X
X
X
Response, Pathological, Biopsy
X
X8
Quality of Life Questions
X
X
X9
Adverse Events
X
X
X


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Baseline1
Day 0
Infusion
Day 1
Treatment
~1 Week 
Post 
Treatment
~4-6 Weeks 
Post Treatment
~12-16 Weeks 
Post Treatment
Follow-Up2
1
Performed within 45 days prior to first dose of study drug.
2
These follow-up to 2 years. 
3
Height collected at baseline only.
4
Blood will be collected Pre-infusion.
5
Hematology (CBC/automated differential: WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, %neutrophils, abs. neutrophils, %monocytes, abs. monocytes, 
%eosinophils, abs. eosinophils, %basophils, abs. basophils, %lymph T, abs. lymph T, platelet confirmation as clinically indicated, & differential confirmation as 
clinically indicated).
6
Chemistry (i.e., complete metabolic panel (CMP): chloride, Co2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
7
Refer to Section 8.10.
8
Biopsy for response will be performed during routine visits, only if clinically indicated, and at 2 years.
9
At 6, 12, 18 and 24 months.
10
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Table 3
Schedule of Procedures and Observations for Participants Randomized to Surgery
Baseline1
Day 0
Day 1
Surgery
About 
1 Week 
Post 
Surgery
About 
4-6 W 
Post 
Surgery
About 12-16 W 
Post Surgery
Follow-
Up2
History, Physical
X
Clinical Exam (with 
photograph of lesion if possible)
X
X
X
X
X
Confirm tumor staging with CT 
or MRI scans of the head and 
neck and chest
X
X8
Vital Signs (i.e., temperature, 
heart rate, respiratory rate, 
blood pressure, body weight, 
and height)3
X
X
X
X
X
X
X
Hematology4
X
Chemistry5
X
Biopsy (diagnosis)
X
HCG urine or serum for 
women of childbearing 
potential
X
Toxicity Grade
X
X
Performance Status/ECOG
X
X
X
Response, Clinical
(Evaluate Lesion Size)
X
X
X
Response, Pathological, Biopsy
X
X6
Quality of Life Questionnaire
X
X
X7
Adverse Events
X
X
1.
Performed within 12 weeks prior to surgery.
2.
These follow-up visits will be according to the NCCN guidelines for T1/T2 SCC of head and neck.
3.
Height collected at baseline only.
4.
Hematology (CBC/automated differential: WBC, RBC, HGB, HCT, platelet, MCV, MCH, MCHC, %neutrophils, abs. 
neutrophils, %monocytes, abs. monocytes, %eosinophils, abs. eosinophils, %basophils, abs. basophils, %lymph T, abs. 
lymph T, platelet confirmation as clinically indicated, & differential confirmation as clinically indicated).
5.
Chemistry (i.e., complete metabolic panel (CMP): chloride, Co2, potassium, sodium, BUN, glucose, calcium, creatinine, 
total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), 
anion gap).
6.
Biopsy for response will be performed during routine visits, only if clinically indicated, and at 2 years.
7.
At 6, 12, 18 and 24 months.
8.
CT or MRI as clinically indicated.
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8.10 CORRELATIVE STUDIES SAMPLE COLLECTION AND PROCESSING
8.10.1 Immune Monitoring for Isolation and Storage of Immune Cells
This assay will be performed only for participants randomized to PDT with HPPH. Whole blood 
samples for immune monitoring for isolation and storage of immune cells will be collected via 
venipuncture using (1) 10 mL green-top heparinized collection tube. If possible, sample collection 
will be obtained at the following time points:

Prior to infusion of HPPH on Day 0

About 1 week after the infusion of HPPH

About 4 – 6 weeks after the infusion of HPPH
Whole blood samples collected at RPCI will be sent at room temperature for processing the same 
day of collection.
Whole blood samples collected at participating sites will be shipped at room temperature on the 
day of collection Monday - Thursday. Do not ship specimens on Fridays or on day before a 
holiday.  Samples should be clearly labelled with study #, patient initials, subject ID #, date of 
collection, source of material, (i.e. blood, serum) and sample time point (i.e. prior to infusion of 
HPPH, Day 0), Each subject should have their samples entered on a Network Specimen Requistion 
Form (Other) provided for you along with e-mail notification to Dr. Gollnick; 
Sandra.Gollnick@RoswellPark.org and crsnetworkcoordinators@roswellpark.org
The samples should be sent to:
Roswell Park Cancer Institute
Attn: Flow Cytometry – I 33616
Elm & Carlton Streets
Buffalo, New York 14263
716-845 3528 (8:30 am -5 pm)
joseph.tario@Roswellpark.org and flowlab@roswellpark.org
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
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8.10.2 Photosensitizer (HPPH) and Biomarker (Serum Alkaline DNase) Levels in Serum
This assay will be performed only for participants randomized to PDT with HPPH. Blood for 
determination of photosensitizer and biomarker levels will be collected via venipuncture using (1) 
10 mL red-top collection tube. Whole blood should be allowed to clot and serum isolated via 
centrifugation. Caution should be used to prevent hemolysis. Sample collection will be obtained 
at the following time points:

Prior to infusion of HPPH on Day 0

About 1 week after the infusion of HPPH

About 4 – 6 weeks after the infusion of HPPH
Whole blood samples collected at RPCI will be picked up at room temperature for processing in 
Dr. Bellnier’s laboratory the same day of collection.
Serum will be isolated per network site’s SOP specific to their centrifuge. Isolated serum samples 
from participating sites will be frozen at site (-80C) and stored at site until notified by Network 
coordinator to batch ship all three-time points for each subject. Each patient will have a Network 
Specimen Requisition Form (Other) filled out and included in the shipment. Ship only on Monday-
Thursday. Do not ship specimens on Fridays or on day before a holiday. Samples should be clearly 
labelled with study #, patient initials, subject ID #, date of collection, source of material, (i.e. blood, 
serum) and sample time point (i.e. prior to infusion of HPPH, Day 0), with e-mail notification:
Roswell Park Cancer Institute
Department of Cells Stress Biology
Attn: Dr. David Bellnier – I 33616
Elm & Carlton Streets
Buffalo, New York 14263
716-845-7679 or 716-845-3551
David.Bellnier@RoswellPark.org and crsnetworkcoordinators@roswellpark.org
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.10.3 Diffuse reflectance optical spectroscopy
This assay will be performed only for participants randomized to PDT with HPPH. Non-invasive 
reflectance spectroscopy will be performed to assess HPPH concentration, blood volume, and 
blood SO2 within the lesion before and immediately after PDT. We will use the reflectance system 
marketed by Zenalux (Zenascope). This device has been approved by the IRB at RPCI for use in 
two ongoing clinical studies (I 235613 and I 239713). A short description of the system and the 
scientific rationale are provided in Appendix B.
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The measurements will be done by placing the measurement probe (5 mm in diameter) in contact 
with the surface of the lesion for a few seconds. The probe will deliver low-intensity white light 
to the lesion and detect the reflected light. A total of 3-5 measurements will be taken from the 
center of each lesion, before and immediately after PDT. The data set will be identified by the 
participant’s ID and stored on a secure laptop. The end of the probe will be disinfected after use in 
each participant by soaking it in Cidex for 15 minutes following the procedure described in 
Appendix C.
8.11 PATHOLOGY
At each site, the tumor biopsy will be sent to a surgical pathologist and processed for routine 
standard of care pathological examination. When tumor-biopsy morphology precludes objective 
evaluation by histopathology, ancillary immunohistochemical studies may be employed to 
determine the presence of tumor cells, by the pathologist. (If standard H&E cannot be used to 
evaluate the presence of tumor cells, the pathologist will use immunohistochemistry to evaluate 
the biopsy).
8.12 CLINICAL
Dr. Biel, a Project Leader at the University of MN will be available for consultation throughout 
the study.  
Ear, Nose & Throat Specialty Care of Minnesota
Dr. Merrill Biel
2211 Park Avenue South
Minneapolis, MN 55404
Tel. 612-871-2980 or Cellphone: 612-501-8535
Fax: 612-871-2012 or E-mail: bielx001@umn.edu 
9
EFFICACY EVALUATIONS
9.1
OBJECTIVE TUMOR RESPONSE
Pathological tumor response will be evaluated by taking a 3-mm punch biopsy from the PDT 
treated or surgical area at 12-16 weeks after PDT or surgery. The participants from the PDT and 
surgery arms will be followed clinically up to 2 years. At the end of the follow up time, the treating 
physician will examine the clinical response and a photograph of the treatment site will be taken 
with paper ruler, to determine the reduction in the lesion size, according to RECIST v1.1. The 
study coordinator or nurse will take the photos. The treating physician will determine the lesion 
size with a caliper if photos can't be taken.
9.2
TARGET LESIONS
All identifiable lesions will be recorded with digital photography and clinical examination. The 
objective tumor response will be determined according to the following criteria per Recist v1.1:

Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must 
have a reduction in short axis to < 10 mm.
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
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. A biopsy will be taken from the suspected 
lesions for histological confirmation of squamous cell carcinoma.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance of one or more new 
lesions is also considered progression.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study, the 
response will be listed with stable disease. In this case, a biopsy will be taken from the 
suspected lesion for histological confirmation.
9.3
EVALUATION OF RESPONSE
Time point response assessments will be performed 12 - 16 weeks and 24 months after PDT. To 
determine time point response, refer to Table 4 below.
Table 4
Time Point Response Criteria (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
The best overall response is the best response recorded from the start of study treatment until 
follow-up is completed or the participant goes off study (the end of treatment taking into account 
any requirement for confirmation).

Symptomatic Deterioration: Participants with global deterioration of health status requiring 
study withdrawal without objective evidence of disease progression at that time, and not related 
to study treatment or other medical conditions should be reported as progressive disease due 
to “symptomatic deterioration.” Every effort should be made to document objective 
progression even after discontinuation of treatment due to symptomatic deterioration. 
Symptomatic deterioration that may lead to study withdrawal includes, but is not limited to, 
symptoms such as:
o
Weight loss > 10% of body weight.
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o
Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).
o
Decline in performance status of > 1 level on ECOG scale.
10 SAFETY EVALUATION
10.1 ADVERSE EVENTS
10.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
10.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
10.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
10.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
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If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
10.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
10.1.2 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology and graded according to definitions provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical state, 
other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most likely 
related to other factors such as the participant’s clinical state, other therapeutic interventions, 
or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot be 
reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs.
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
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.
10.1.3 Reporting Routine Adverse Events
Table 5
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the start of intervention until 30 days after the last intervention or 
until the event has resolved, stabilized, death, or a new treatment is started, whichever comes first, 
will be reported. New information will be reported after it is received.
Photolitec, LLC. Buffalo, NY will be receiving copies of all the reports (de-identified).
10.2 SERIOUS ADVERSE EVENTS
10.2.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours)

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly or birth defect

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above
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10.2.2 Reporting Serious Adverse Events
All new SAEs occurring from the date of the HPPH study drug infusion until 30 days after the 
HPPH Drug infusion, or PDT light treatment, will be reported to the IRB, in accordance to RPCI 
guidelines. The RPCI SAE Source Form is to be completed with all available information, 
including a brief narrative describing the SAE and any other relevant information.
SAEs occurring after the 30 day follow up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAE’s identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 10.5for details on reporting Unanticipated Problems.
10.3 INVESTIGATOR REPORTING: NOTIFYING PHOTOLITEC LLC
The investigator at each site will notify Photolitec, LLC. Buffalo, NY on the occurrences of 
reportable safety issues by sending de-identified copies of the safety reports to: 
Ravindra K. Pandey, PhD
Chief Scientific Officer
Photolitec, LLC
73 High Street
Room # 115
Buffalo, NY 14203
Ravindra.Pandey@RoswellPark.org
(Office Phone) 716.854.1030
(Cell phone) 716.345-9348
FAX# 716-845-8920
Secondary Photolitec Contact:
Pascal Soares, V.P Business Development
email address: Psoares@photolitec.org
10.4 FOLLOW-UP FOR SERIOUS ADVERSE EVENTS
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
10.5 UNANTICIPATED PROBLEMS
10.5.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
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a) The research procedures that are described in the study-related documents, including study 
deviations, as well as issues related to compromise of participant privacy or confidentiality 
of data.
b) The characteristics of the population being studied.

Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized 
and if in relation to an AE is also deemed Serious per Section 10.2.
10.5.2 Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Reportable New 
Information (RNI) Form will be submitted to CRS Compliance Office within 1 business day of 
becoming aware of the Unanticipated Problem. After review, CRS Compliance will submit the 
RNI to the IRB.
When becoming aware of new information about the Unanticipated Problem, submit this updated 
information to CRS Compliance with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems, whether 
related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
10.6 SAFETY STOPPING RULE
If 20% of patients randomized to the PDT arm fail treatment and require salvage surgery at any 
one institution with 50% of their accrual target, the RPCI DSMB will suspend the study for further 
evaluation.
10.7 FDA REPORTING
This protocol is being conducted under a RPCI IND, and RPCI will be responsible for reporting 
certain AEs or Unanticipated Problems to the FDA. RPCI’s Compliance Office will report 
Network Site reports to the FDA.
The following describes the FDA reporting requirements by timeline for AEs and new safety 
findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Fatal or life-threatening.
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Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Serious but not fatal or life-threatening.
Or meets ANY of the following criteria:

A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).

Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.

Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or reports 
of significant organ toxicity at or near the expected human exposure.

Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning similar 
adverse events and to analyze the significance of the current event in the light of the previous 
reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Compliance Office 
via email: CRSCompliance@RoswellPark.org.
11 DATA AND SAFETY MONITORING BOARD
The RPCI Data and Safety Monitoring Board will assess the progress of the study, the safety data, 
and critical efficacy endpoints. The DSMB will review the study annually and will make 
recommendations that include but not limited to; (a) continuation of the study, (b) modifications 
to the design (c) or termination of the study.
12 STATISTICAL METHODOLOGY
The primary objective of this study is test the non-inferiority of PDT to standard of care by 
comparing the rate of tumor response after PDT to those obtained after surgery, at 24 months post 
treatment. The secondary objectives are to compare QoL after PDT or surgery at 6, 12, 18, and 24 
months post-procedure, and to assess the toxicity using the CTEP NCI Common Terminology 
Criteria for Adverse Events (CTCAE Version 4.0).
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12.1 JUSTIFICATION FOR THE STATISTICAL DESIGN AND THE NON-
INFERIORITY MARGIN 
In our previously published study we observed an 82% CR in patients with T1/T2 N0 SCC of the 
oral cavity treated with PDT and HPPH.18 We also reported a similar response rate when we used 
HPP-PDT to treat early stage laryngeal cancer.52 These response rates are in agreement with other 
studies using PDT in this indication (see Table 1 in section 1.3). All patients that failed to respond 
were successfully salvaged by surgery. Since the local recurrence rate after initial surgery is as 
high as 20%,7-9 we believe that it is reasonable to assume that 85% CR will be observed in both 
arms. We also wish to provide a bit of a cushion in case the surgical response rate is much higher 
than 85% given we are in an experimental setting.
In addition, we propose using the logic and rational the FDA guidance documents propose for 
traditional phase III bioequivalence trials in terms of our trial design. The FDA refers to various 
rules such as the 80/20 rule, 75/75 rule, where the generic drug needs to be within 20% of the 
brand product relative to specified pharmaceutical measures. For a phase III trial the standard 
80/20 rule translates to approximately a 17 percentage point difference. The 75/75 rule yields 
roughly a 21 percentage point difference. Hence, in the phase II setting we believe a 20-point 
difference is reasonable in terms of determining whether or not a confirmatory large-scale phase 
III trial with a tighter equivalence window should be put forward as a next step. The information 
gained form this study will be used for a larger scale phase III equivalence trial in terms of planning 
and sample size calculations with a tighter equivalence threshold. In terms of safety, it should be 
noted that patients that fail PDT can be effectively salvaged with surgery, in a timely manner.    
12.2 SAMPLE SIZE DETERMINATION
In the proposed randomized trial, participants will be randomized to the treatment arms using a 
stratified block randomization scheme, with blocking stratified by clinical site (RPCI, and two 
other participating sites). Participants will be included in data analyses according to their 
randomized treatment assignment irrespective of the treatment actually received (intent-to-treat). 
Exceptions would include those who withdraw their consent to use any of their data prior to 
receiving any study medication. Initiation of study treatment will take place as soon as possible 
following randomization. No method of imputation will be used for missing data. All available 
data from participants who fail to complete this study will be included in all safety summaries.
The safety of the interventions will be assessed through the evaluation of Grade 3 or higher 
toxicities deemed possibly related to treatment. Both efficacy (e.g., tumor response) and toxicity 
rates will be estimated using simple relative frequencies. The corresponding 95% confidence 
intervals for the estimated probabilities will be computed using the method proposed in Clopper 
and Pearson (1934).
The design for this study is based on a test for non-inferiority of PDT compared to standard of care 
with regards to tumor response at 24 months post-procedure. Justification for use of a non-
inferiority trial is that PDT may be viewed as a potential replacement for standard of care if it is 
established as less toxic than the standard of care yet still providing acceptable efficacy. Let 
SOC

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and 
PDT

 are the probabilities of tumor response in the standard of care and PDT groups, 
respectively. The hypotheses corresponding to the proposed non-inferiority trial are 
0 :
,
:
,
PDT
SOC
a
PDT
SOC
H
H








where  is the non-inferiority margin. Specifically, we will be using the approach of Farrington-
Manning to test our hypothesis via a score based test.53 
Under the null hypothesis (
PDT
SOC





) is the probability of observing a particular set of 
results. A non-inferiority margin of 20 percentage points will be utilized and the Farrington-
Manning based test will be performed in conjunction with a 0.05 nominal significance level. In 
the event that the non-inferiority test is statistically significant, a test for superiority will be 
conducted. The samples sizes of the trial are set at 57 in the standard of care and PDT groups. With 
the proposed sample sizes, there is approximately 80% power associated with the non-inferiority 
test when the true tumor response probabilities are equal to 85% in both groups. The calculation 
was carried forth using SAS PROC POWER.
In the analysis of QoL simple data analyses will initially take place including individual 
participant-level profile plots and overall mean plots used to examining the mean structure. 
Formal statistical examination of longitudinal patterns will be done through the use of a mixed 
model. Restricted maximum likelihood estimation will be utilized in the model fitting procedures 
as implemented by SAS PROC MIXED (version 9.3). Once the model is fit, specific linear 
contrasts based on the estimated model parameters will be constructed and used to test 
hypotheses concerning between time points and between group comparisons. We acknowledge 
the possibility of informative missingness, that is, the probability of a particular observation 
being missing may be related to the health of the participant, and therefore analyses will be 
interpreted with caution. All tests will be two-sided and tested at a 0.05 nominal significance 
level. Standard diagnostic plots will be used to assess model fit and transformations of variables 
may be considered in order to meet statistical assumptions.
12.3 EFFICACY ANALYSIS
Objective tumor response will be tabulated overall. All participants who will be randomized to the 
PDT treatment or surgery will be evaluable for response. Tumor response will be evaluated 
according to RECIST v1.1. The treating physician will examine the clinical response and a 
photograph of the treatment site/s will be taken with paper ruler, to determine the reduction in the 
lesion size. Tumor response will be determined according to the guidelines in sections 9.2 and 9.3. 
If clinically indicated, the clinical evaluation will be confirmed with pathological examination of 
tissue 3-mm punch biopsy that will be taken from the treated region.
12.4 ADVERSE EVENT
The frequency of toxicities will be tabulated by grade. All participants who receive any study 
treatment will be considered evaluable for toxicity.
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RPCI may terminate the study at any time upon immediate notice if it believes termination is 
necessary for the safety of participants enrolled in the study.
12.5 INTERIM ANALYSIS AND CRITERIA FOR EARLY TERMINATION OF THE 
STUDY
No interim analysis is planned for this study.
13 ETHICAL AND REGULATORY STANDARDS
13.1 ETHICAL PRINCIPLES
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
13.2 INFORMED CONSENT
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant or the participant's legally authorized representative in accordance with applicable GCP 
guidelines using the approved informed consent form, before any study specific procedures 
(including screening procedures) are performed. The informed consent form acknowledges all 
information that must be given to the participant according to GCP guidelines, including the 
purpose and nature of the study, the expected efficacy and possible side effects of the treatment(s), 
and specifying that refusal to participate will not influence further options for therapy. Any 
additional information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is allowed.
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The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
14 STUDY RESPONSIBILITIES
14.1 DATA COLLECTION
Data entry into the database is to be completed in a timely fashion (within 30 days) after the 
participant’s clinic visit. If an AE is considered serious it is captured on both the Adverse Event 
page and the Serious Adverse Event Form, which is handled in an expedited fashion).
Data management activities will be performed using EXPeRT. EXPeRT is a suite of software tools 
that enables the collection, cleaning and viewing of clinical trial data. CRS data management will 
design the study-specific database and facilitate its development by the eClinical Information 
Technology team. Once the database design is approved by the Investigator, Statistician, and 
Clinical Research Coordinator, the database will be put into production and data entry can begin. 
Data can be entered and changed only by those with the rights to do so into the eCRFs (via EXPeRT 
Module). eClinical is compliant with all relevant technical aspects of relevant GCP guidelines.

The system can generate accurate copies of stored data and audit trail information in human 
readable form.

System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.

The system is designed to periodically force users to change their passwords and verifies 
that user ID and password combinations remain unique.

The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
14.2 MAINTENANCE OF STUDY DOCUMENTS
Essential documents should be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the applicable 
local regulatory requirements or by an agreement with RPCI.
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15 ADMINISTRATIVE RULES
15.1 REVISIONS TO THE PROTOCOL
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
15.2 TERMINATION OF THE STUDY
It is agreed that, for reasonable cause, either the Investigators or the Sponsor, RPCI may terminate 
this study, provided a written notice is submitted within the time period provided for in the Clinical 
Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice if 
it believes termination is necessary for the safety of patients enrolled in the study.
15.3 CONFIDENTIALITY
Any data, specimens, forms, reports, photos, and other records that leave the site will be identified 
only by a participant identification number (Participant ID, PID) to maintain confidentiality. All 
records will be kept in a limited access environment. All computer entry and networking programs 
will be done using PIDs only. Information will not be released without written authorization of the 
participant.
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16 APPENDICES
Appendix A. Instructions for Network Sites
1. CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 8:00 AM to 4:30 PM EST
716-845-3155
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2. INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any participant, 
or their legally authorized representative, wishing to participate, prior to any procedures or 
treatment.

An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.

All consent changes must be reviewed by RPCI Network Office prior to submission to the 
site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being used.

Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3. PARTICIPANT REGISTRATION
The participant, or their legally authorized representative, completes the Gender, Race, and 
Ethnicity Form and this is placed in the study binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Screening and Enrollment Log must be faxed to the RPCI Network Office within 1 business 
day of the date the participant is consented. Once the Investigator has determined that eligibility 
has been met, complete the Subject Registration Form and fax it to the RPCI Network Monitor at 
716-845-8743.
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Protocol Randomization Instructions
4. Patients at Roswell Park Cancer Institute will be registered directly by Roswell staff using the 
web-based registration system. For patients at institutions outside Roswell Park Cancer 
Institute, the local site staff will contact the appropriate coordinator to register the patient using 
the web-based registration application as developed by the GOG Foundation Statistical & Data 
Management Center in conjunction with the study biostatistician. Within 24 hours the Network 
Monitor will email the randomization arm assignment and network participant ID # back to 
the site PI. The site PI will send a confirmation email back to the Network Monitor verifying 
the randomization arm for the specified network participant. Questions regarding 
randomization 
issues 
can 
be 
emailed 
to 
alan.hutson@roswellpark.org 
or 
william.brady@roswellpark.org. 
5. STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the RPCI Network, 
site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.
6. STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not allowed.

If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.
o
Do NOT use white-out, magic marker, scratch-outs.
o
Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of RPCI to inform the Investigator/institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
7. DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.
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
Drug accountability forms are protocol and agent specific, they are study source documents 
and will be used to verify compliance with the study.

An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have its 
own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
8. SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. A preliminary written report must follow within 1 business day of the first 
notification using the following forms:

RPCI SAE Source form

MedWatch Form FDA 3500A- This protocol is being conducted under a RPCI IND, please 
refer to Section 10.7 of the protocol FDA Reporting for timelines of reporting.

Notify Photolitec:
Dr. Ravinda K. Pandey  
email address: Ravinda.Pandey@Roswellpark.org  FAX# 716-845-8920
Secondary Photolitec Contact:
Pascal Soares, V.P Business Development
email address: Psoares@photolitec.org
A complete follow-up report must be sent to the RPCI Network Monitor when new information 
becomes available.
9. UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 10.5.1. Network sites follow the instructions below for reporting a UP to the Network 
monitor. RPCI compliance will report the information to the FDA.( Section 10.7)
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the RPCI Network Monitor within 1 business day of being made aware of the 
Unanticipated Problem by completing the RPCI Unanticipated Problem Report Form and 
faxing or emailing it to the RPCI Network Monitor.
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Appendix B. Spectroscopy
In participants where the lesion location permits use of a non-invasive spectroscopy probe, 
quantitative diffuse reflectance spectroscopy measurements will be performed immediately prior 
to and immediately following PDT. The information extracted from these measurements includes 
hemoglobin oxygen saturation (SO2), blood volume, and HPPH concentration.
Intriguing preliminary associations have emerged between several of these metrics and treatment 
response, but the small number of treatment failures precludes any firm conclusions based on our 
previously published Phase I results (Rigual, Shafirstein et al. Clinical Cancer Res 2013). In 
keeping with our central focus of establishing PDT as a mainstream option for head and neck 
cancer, the spectroscopy device to be deployed to sites outside of Roswell Park will be the 
reflectance system marketed by Zenalux Biomedical, Inc. This system is inexpensive, compact, 
and has been rigorously characterized by our collaborators at the University of Rochester (Drs. 
Foster and Baran). The Zenalux system is available widely to clinicians. It is fully capable of 
acquiring the reflectance data necessary to test the hypotheses that one of a combination of initial 
HPPH levels, blood volume, and hemoglobin oxygen saturation are useful predictors of tumor 
response to HPPH PDT.
Each of the above-mentioned parameters offers the potential to report something important about 
a tumor’s amenability to PDT and/or its response to a treatment. For example, because the 
photochemistry of PDT relies on oxygen, one would predict that relatively high SO2 at the time of 
treatment would predict for a good response. Similarly, a higher photosensitizer concentration 
would be an indicator that likely predicts for a favorable response. Therapy-induced reductions in 
tumor blood volume and the details of the time course of blood volume reduction have been useful 
reporters in pre-clinical models. This creates a significant clinical research opportunity to identify 
readily accessible, non-invasive surrogate optical reporters of treatment response, which may 
eventually help to identify which participants may require follow-up PDT or some other 
intervention following an initial treatment. Thus, there is a strong scientific rationale for the use of 
these forms of optical spectroscopy studies.
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Appendix C
Chemical Sterilization
High Level Disinfection using Cidex, for the Frieburg Flap or reflectance spectroscopy probe 
that will be used in the measurements described in Section 8.10.3, will be performed with the 
following steps:

Cidex must be used under a hood (ventilation hood is required): avoid inhalation. 

Wear protective gloves- do not allow to touch hands, or to splash in eyes.

Prior to placing in the Cidex: the spectroscopy probe must be thoroughly cleaned of any 
debris, blood, and other bodily fluids.

Immerse the distal end of the spectroscopy probe in Cidex solution for 15 minutes (item 
must be completely immersed).

Remove from Cidex solution (wearing gloves for protection).

Rinse the probe thoroughly with sterile water- all Cidex must be removed by rinsing.

Pat dry with sterile towel or sterile gauze.

Place in sterilization bag or baggie.
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Appendix D
ECOG Performance Status
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix E
Toxicity Serious Adverse Event Reports
An evaluation of toxic response to HPPH administration will be performed on all participants 
treated under this protocol. Responses will be graded based upon the classification criteria listed 
in the Common Terminology Criteria for Adverse Events, Version 4.0.
The following scale will be used for systemic toxicity:
Description
Grade
Acceptable
Grade 0, Grade 1, Grade 2
Unacceptable
Grade 3 or higher
Adverse events will be graded and recorded in the electronic database. Serious Adverse Events 
will be reported on the SAE Reporting Form.
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Appendix F
Normal Tissue Toxicity Grading
Effect
Score
No change.
0
Mild erythema and/or mild edema.
1.0
Moderate erythema and/or moderate edema (ability to eat solid foods).
1.5
Extensive erythema and/or extensive edema (requires liquid diet).
2.0
Severe edema (no alimentation possible), ulceration >>4 mm in depth (as determined by 
the physician).
3.0
Respiratory distress due to edema), ulceration >>4 mm in depth (as determined by the 
physician).
4.0
Note: In some cases the normal tissue toxicity may not be possible to judge if no normal tissue is in the light field.
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Appendix G. Correlative Studies (if possible)
Examination of Induction of Anti-Tumor Immunity in Participants Treated with PDT
In order to determine whether PDT enhances anti-tumor immunity a three-pronged analysis will 
be performed. The effect of PDT on T cell activity will be initially be determined by examining 
the activation status of participant T cells before and after PDT administration. PDT induces a 
rapid pro-inflammatory response; such responses are associated with T cell activation and 
proliferation, which are frequently muted in participants with advanced cancer. T cell activation 
will be determined by flow cytometric analysis of peripheral blood T cells. Using T cell subtype 
and activation specific profiles, this analysis will allow us to determine whether administration of 
PDT alters both the activation status and ratio of T Cell subtypes present before and after therapy.
The phenotypic characterization described above will determine whether PDT affects T cell 
activation and subtype ratio but will not discern whether the effects are tumor specific. Most 
tumors over-express p53 and many head and neck tumors overexpress HPV 16. Examination of 
changes in the immune response to p53 and/or hpv 16 can reveal changes in tumor specific immune 
responses. To examine whether PDT enhances the immune response to p53 or HPV 16, peripheral 
blood T cells will be isolated and exposed to p53 and HPV 16 ex vivo. The ability of each 
participant’s T cells to respond will be measured over time and compared against pre-treatment 
results and to their ability to respond to antigens they have previously been exposed to, 
i.e., cytomegalovirus, Epstein-Barr virus and influenza virus (the so-called memory mix).
The second method for examining tumor specific T cells following PDT involves adding an 
additional marker to the flow panels described above. There is a well-defined p53 immune epitope 
that binds to the human major histocompatibility complex molecule HLAA2. Greater than 40% of 
the patients at RPCI express HLA-A2. HLA-A2 expression status of the trial participants will be 
determined. T cells isolated from HLA-A2+ participants will be tested for p53 reactivity using a 
flow cytometry reagent known as a tetramer that allows identification of p53 specific T cells.
The methods described above will determine whether PDT enhances T cell responses. To 
determine whether there is an increase in humoral (B cell) responses to tumors following 
administration of PDT changes in the levels of circulating antibodies against p53 and HPV 16 will 
be 
measured. 
(Network 
sites 
to 
inform 
Dr. 
Sandra 
Gollnick 
and 
crsnetworkcoordinators@roswellpark.org and ship to Flow Cytometry - see shipping instructions 
in section 8.10.1). Do not ship specimens on Fridays or on a day before a holiday. 
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Appendix H
Appendix H. University of Washington Quality of Life Questionnaire version 
4 (UW-QoLQ v4)
Date: ___/___/____
Subject ID#______________
This questionnaire asks about your health and quality of life over the past seven days. Please 
answer all of the questions by checking one box for each question.
1.
Pain (Check one box: )

I have no pain.

There is mild pain not needing medication.

I have moderate pain - requires regular medication (codeine or nonnarcotic).

I have severe pain controlled only by narcotics.

I have severe pain, not controlled by medication.
2.
Appearance (Check one box: )

There is no change in my appearance.

The change in my appearance is minor.

My appearance bothers me but I remain active.

I feel significantly disfigured and limit my activities due to my appearance.

I cannot be with people due to my appearance.
3.
Activity (Check one box: )

I am as active as I have ever been.

There are times when I can't keep up my old pace, but not often.

I am often tired and have slowed down my activities although I still get out.

I don't go out because I don't have the strength.

I am usually in bed or chair and don't leave home.
4.
Recreation (Check one box: )

There are no limitations to recreation at home or away from home.

There are a few things I can't do but I still get out and enjoy life.

There are many times when I wish I could get out more, but I'm not up to it.

There are severe limitations to what I can do, mostly I stay at home & watch TV.

I can't do anything enjoyable.
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5.
Swallowing (Check one box: )

I can swallow as well as ever.

I cannot swallow certain solid foods.

I can only swallow liquid food.

I cannot swallow because it "goes down the wrong way" and chokes me.
6.
Chewing (Check one box: )

I can chew as well as ever.

I can eat soft solids but cannot chew some foods.

I cannot even chew soft solids.
7.
Speech (Check one box: )

My speech is the same as always.

I have difficulty saying some words but I can be understood over the phone.

Only my family and friends can understand me.

I cannot be understood.
8.
Shoulder (Check one box: )

I have no problem with my shoulder.

My shoulder is stiff but it has not affected my activity or strength.

Pain or weakness in my shoulder has caused me to change my work.

I cannot work due to problems with my shoulder.
9.
Taste (Check one box: )

I can taste food normally.

I can taste most foods normally.

I can taste some foods.

I cannot taste any foods.
10.
Saliva (Check one box: )

My saliva is of normal consistency.

I have less saliva than normal, but it is enough. 

I have too little saliva. 

I have no saliva.
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11.
Mood (Check one box: )

My mood is excellent and unaffected by my cancer.

My mood is generally good and only occasionally affected by my cancer.

I am neither in a good mood nor depressed about my cancer.

I am somewhat depressed about my cancer.

I am extremely depressed about my cancer.
12.
Anxiety (Check one box: )

I am not anxious about my cancer.

I am a little anxious about my cancer.

I am anxious about my cancer.

I am very anxious about my cancer.
Which issues have been the most important to you during the past 7 days?
Check  up to 3 boxes.

Pain

Swallowing

Taste

Appearance

Chewing

Saliva

Activity

Speech
Mood

Recreation

Shoulder

Anxiety
GENERAL QUESTIONS
Compared to the month before you developed cancer, how would you rate your health-related 
quality of life? (check one box: )

Much better

Somewhat better

About the same 

Somewhat worse

Much worse
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In general, would you say your health-related quality of life during the past 7 days has been: (check 
one box: )

Outstanding

Very good

Good

Fair

Poor

Very poor
Overall quality of life includes not only physical and mental health, but also many other factors, 
such as family, friends, spirituality, or personal leisure activities that are important to your 
enjoyment of life. Considering everything in your life that contributes to your personal well-being, 
rate your overall quality of life during the past 7 days. (Check one box: )

Outstanding

Very good

Good

Fair

Poor

Very poor
Please describe any other issues (medical or nonmedical) that are important to your quality of life 
and have not been adequately addressed by our questions (you may attach additional sheets if 
needed).
Signature____________________________________
Printed name_________________________________
Date________________________________________
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