Conditions: Brain Tumor, Recurrent
Keywords: Brain Tumor Photodynamic Therapy Photochemotherapy Astrocytoma Pilocytic Astrocytoma Low grade Astrocytoma Anaplastic Astrocytoma Glioblastoma GBM Chordoma Germinoma Germ Cell Tumor Non-germinoma CNS Lymphoma Craniopharyngioma Mixed Glioma Optic Nerve Glioma Meningioma Oligodendroglioma Pituitary Tumors Desmoplastic Neuroepithelial Tumor DNET glioblastoma multiforme glioma glioblastoma survivors what is glioblastoma gbm cancer oligoastrocytoma gbm tumor anaplastic oligodendroglioma High-Grade Glioma high grade glioma glioblastomas glioblastoma cancer anaplastic oligoastrocytoma astrocytoma glioma glioblastoma clinical trials photodynamic therapy for cancer glioblastoma multiforme clinical trials astrocytoma glioblastoma gbm grade 4 clinical trials for glioblastoma photodynamic therapy cancer clinical trials glioblastoma glioblastoma clinical trials 2015 glioblastoma clinical trials 2014 not open in 2014 glioblastoma trials gbm clinical trials glioblastoma immunotherapy malignant gliomas anaplastic astrocytomas immunotherapy for glioblastoma immunotherapy glioblastoma High Grade Glioblastoma Multiforme clinical trial glioblastoma glioblastoma clinical trial glioblastoma trial brain tumors recurrent brain tumors glioma grade 3 grade 3 brain tumor grade 4 brain tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This study will be aimed at investigating the effectiveness of a treatment for brain tumors called Photodynamic Therapy, or PDT. Briefly, a subject will receive a light-sensitive drug, called Photofrin®, the day before a tumor removal surgery. The next day, after the tumor is removed, red light from a laser will be shone into the tumor cavity through a light-diffusing sphere. This light will activate the photosensitizer, and possibly kill any tumor cells that may be left.

We plan to measure how long the subject may go without a new tumor regrowth, and overall how long subjects survive. We will compare these results to typical results to see if we are seeing any improvements.

Objective: To define the antitumor activity of Photofrin® and laser light activation within the confines of a Phase II study.

Detailed description:
Photodynamic therapy (PDT) is a well-known treatment for other type of tumors; however it is an experimental treatment for brain tumors. There is much we do not know about the effectiveness of PDT in patients with brain tumors. The purpose of this study is to define the antitumor activity of Photofrin® and laser light activation. Photofrin® is a photosensitizing drug (a dye that is activated by light) used in PDT. We want to test the activity of PDT and to see what are the effects (good and bad) on you and your brain tumor. We also want to learn if this treatment will cause brain tumors to shrink and whether it will help patients with brain tumors to live longer.

PDT is a cancer treatment that involves giving a photosensitive dye (Photofrin®), into your vein through a tube (called an IV). This dye will go inside of the cancer cells more than it will go inside the normal, healthy cells. PDT using Photofrin® is an approved treatment in patients with certain types of cancer such as lung, and esophageal (from the mouth to the stomach) cancers.

Everyone in this study will receive Photofrin® (porfimer sodium) for injection (Pinnacle Biologics, Inc., Bannockburn, IL, USA), and be treated with red light emitted by a red laser. The light will be sent from the laser to the surface of the brain where the tumor is located using a light transmitting fiber. The fiber will have a knob at the end that spreads the light out evenly in all directions.

Previous studies have shown that patients with malignant brain tumors called gliomas had a good response to PDT. The patients in these studies lived longer than they were expected to live. In one study of adults with brain tumors in Australia, patients given PDT had greatly improved survival rates. Fifty seven percent (57%) of the patients with gliomas called anaplastic astrocytoma survived for 36 months. Thirty seven percent (37%) of the patients with gliomas called glioblastoma multiforme survived for 36 months. Froedtert Hospital, in Milwaukee WI, has been involved in PDT studies in adults in the past. This current study is is being done in a very similar way to the study done in Australia, and will use increased Photofrin®) and light doses than our previous study.

Arms:
arm 1: Photofrin photodynamic therapy. Drug - 2.5 mg/kg, light - 240 mJ/cm2.

Interventions: intervention 1: Photofrin photodynamic therapy.
Intervention descriptions: intervention 1: The subjects will receive a dose of 2.5 mg/kg of Photofrin intravenously 24 hours before planned surgical resection. Tumor resection will be carried out in the standard fashion in order to achieve the maximum tumor resection compatible with preservation of neurological function. After resection, Intralipid will be infused into the craniotomy and kept for approximately 45 min, while PDT will be performed. The illumination time will be calculated from the power density (mW) emitted by the laser and the radius (r) of the cavity to deliver a total light dose of 240 J/cm2 at a using the following formula:

Treatment Time (sec) = Light dose (J/cm2) x Cavity surface (cm2) x 1000 Power density (mW) Cavity Surface (cm2) = 4 x 3.14 x r2 The optical fiber will be placed in the center of the surgical cavity and photoillumination will commence. After PDT, the Intralipid solution will be removed and the wound will be closed. The subject will be sent to the intensive care area for recovery.

Protocol document:
Prot_SAP_000.pdf: 
PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 1 of 78 
 
 
 
Version No.: 2.0 
 
 
 
 
 
Revision Date:   
12/01/2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase II Study of Photodynamic Therapy (PDT) with Photofrin® (IND 104,613) for 
Recurrent High-Grade Gliomas in Adults 
 
 
 
 
 
SPONSOR INVESTIGATOR 
Harry T. Whelan, MD 
Professor of Neurology 
Medical College of Wisconsin 
Department of Neurology 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone:  (414) 266-7544 
Fax:    (414) 266-3466 
Email:  hwhelan@mcw.edu 
 
 
Funding for this protocol, Photofrin®, a drug approved for use under this IND, and additional 
services are provided by, Pinnacle Biologics Inc., USA, a subsidiary of Concordia Laboratories 
Inc., Barbados.  Additional for this protocol has also been provided through a grant from the 
Froedtert Foundation.  
 
 
FDA IND Number: 
104,613 
ClinicalTrials.gov ID: NCT01966809 
MCW/FH IRB ID: 
PRO00023580 
MCW GC ID:  
FP00005327 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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Section 
Page
STUDY COMMITTEE 
5
PROTOCOL SYNOPSIS 
6
PROTOCOL REVISION HISTORY  
9
LIST OF ABBREVIATIONS 
11
1.0 
GOALS AND OBJECTIVES/SCIENTIFIC AIMS 
13
 
1.1 
Primary Objectives/Aims 
13
 
1.2 
Secondary Objectives/Aims 
13
2.0 
BACKGROUND 
14
 
2.1 
Introduction/Purpose 
14
 
2.2 
Photodynamic Therapy 
14
 
2.3 
Hematoporphyrin Derivative and Photofrin® 
14
 
2.4 
Significance 
15
 
2.5 
Innovation 
17
 
2.6 
Relevant Clinical Data 
18
 
2.7 
Rationale For The Adult Phase II PDT Study 
22
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
23
 
3.1 
Regulatory IRB Approval 
23
 
3.2 
Patient Screening Process and Eligibility Assessment 
23
 
3.3 
Informed Consent 
23
 
3.4 
Patient Registration 
23
 
3.5 
Patients Who Do Not Begin Study Treatment 
24
4.0 
PATIENT ELIGIBILITY 
25
 
4.1 
Inclusion Eligibility Criteria 
25
 
4.2 
Exclusion Eligibility Criteria 
26
5.0 
TREATMENT PLAN 
27
 
5.1 
Overview of the Treatment Plan 
27
 
5.2 
Concomitant Therapy Restrictions 
31
 
5.3 
Modifications For Dose Limiting Toxicities 
31
6.0 
SUPPORTIVE CARE GUIDELINES AND OTHER CONCOMITANT 
THERAPY 
32
 
6.1 
Standard Surgical Risks 
32
 
6.2 
Supportive Care for Intraoperative PDT Risks 
33
 
6.3 
Photofrin® Risks and Guidelines 
34
 
6.4 
Overall Adverse Reaction Profile 
35
 
6.5 
Phlebotomy Risks 
36
 
6.6 
Post Marketing Experience 
36
 
6.7 
Concurrent Anticancer Therapy 
36


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 3 of 78 
Section 
Page
 
6.8 
Other Investigational Agents 
36
7.0 
INVESTIGATIONAL DRUG AND DEVICE INFORMATION  
37
 
7.1 
Photofrin® (porfimer sodium, 75 mg) for Injection 
37
 
7.2 
Photodynamic Therapy (PDT) Lasers 
41
 
7.3 
Photodynamic Therapy Light Diffusers:  Optical Fibers 
41
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
42
 
8.1 
Required Clinical and Laboratory and Disease Evaluations 
42
 
8.2 
Follow-up  
42
9.0 
CRITERIA REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA AND STUDY TERMINATION 
43
 
9.1 
Criteria for Removal from Protocol Therapy 
43
 
9.2 
Off Study Criteria 
43
10.0 
STATISTICAL CONSIDERATIONS 
44
 
10.1 
Study Design 
44
 
10.2 
Sample Size and Study Duration 
44
 
10.3 
Methods of Analysis 
45
 
10.4 
Methods of Analyses for Secondary Objectives 
45
 
10.5 
Inclusion of Genders and Minorities 
45
11.0 
EVALUATION CRITERIA 
46
 
11.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
46
 
11.2 
Methodology to Determine Tumor Measurement 
46
 
11.3 
Response Criteria 
46
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
48
 
12.1 
Purpose 
48
 
12.2 
Expedited Reporting Requirements 
48
 
12.3 
Expedited Reporting the Sponsor Investigator Examples 
50
 
12.4 
Reporting Methods for SAEs 
51
 
12.5 
Reporting Requirements – Investigator Responsibilities 
52
 
12.6 
Additional Protocol Specific Reporting Requirements 
53
 
12.7 
Routine Adverse Event Reporting 
54
13.0 
STUDY DATA COLLECTION AND SAFETY MONITORING 
55
 
13.1 
Data Management 
55
 
13.2 
Case Report Forms 
55
 
13.3 
Data and Safety Monitoring Plan (DSMP) 
56
 
13.4 
Monitoring 
59
 
13.5 
Record Retention 
60
 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
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Section 
Page
14.0 
CONDUCT OF STUDY 
61
 
14.1 
Good Clinical Practice 
61
 
14.2 
Ethical Considerations 
61
REFERENCES 
62
APPENDIX 1 
PDT EVALUATION TABLE 
69
APPENDIX 2 
PATIENT INFORMATION SHEET 
70
APPENDIX 3 
COMMONLY PRESCRIBED PHOTOTOXIC DRUGS 
73
APPENDIX 4 
OVERVIEW OF PUBLISHED LITERATURE:  PHOTODYNAMIC 
THERAPY  
75


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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STUDY COMMITTEE 
PRINCIPAL INVESTIGATOR 
Harry T. Whelan, MD (Sponsor-Investigator) 
Professor of Neurology 
Medical College of Wisconsin 
Department of Neurology 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: 
(414) 266-7544 
Pager: 
(414) 907-3620 
Fax:  
(414) 266-3466 
Email:  
hwhelan@mcw.edu 
EMERGENCY CONTACT 
Phone: 
(414) 266-7544 
Pager: 
(414) 907-3620 
 
NONEMERGENCY CONTACT 
Maureen Bayliss 
Administrative Assistant to Dr. Whelan 
Phone: 
(414) 266-7544 
Fax:  
(414) 266-3466 
Email: 
mbayliss@mcw.edu  
STUDY INVESTIGATORS 
Jennifer Connelly, MD 
Wade Mueller, MD 
Sonia Neuberger, PA-C 
Edit Olasz MD, PhD 
Brendan Quirk, PhD 
Kathleen Schmainda, PhD 
Peter LaViolette, PhD 
James Thomas, MD, PhD 
 
BIOSTATISTICIAN 
Aniko Szabo, PhD 
AFFILIATION 
Neurology/Oncology 
Neurosurgery/Adult 
Neurology/Neuro-Oncology 
Dermatology 
Neurology/Research 
Radiology/Research 
Radiology/Research 
Hematology/Oncology  
 
 
 
Biostatistics/Research 
CLINICAL TRIALS OFFICE 
Medical College of Wisconsin Cancer 
Center Clinical Trials Office (CTO) 
9200 West Wisconsin Avenue 
Milwaukee, WI 53226 
Phone: 
(414) 805-8900 
Fax:  
(414) 805-0596  
Email: 
cccto@mcw.edu 
 
Administrative Director 
Betty Oleson, BSN, RN, CCRP 
COLLABORATORS 
PINNACLE BIOLOGICS INC. 
311 S Wacker Dr., Suite 4990, Chicago, IL 60606 
Phone: 
(847) 283-7690 
Fax:  
(414) 283-7695 
Email:  
info@pinnaclebiolgics.com 
 
A United States based subsidiary of: 
CONCORDIA LABORATORIES INC. 
Canewood Business Centre, 5 Canewood 
Industrial Park, St. Michael, Barbados BB11005 
Tel:  (246) – xxx-xxxx 
Fax:  (246) 621-1860 
Email:  
info@concordiarx.com 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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PROTOCOL SYNOPSIS 
 
Protocol Identifiers. 
ClinicalTrials.gov ID:  
NCT01966809 
IND No.:  
104,613 
MCW/FH IRB:  
PRO00023580 
MCW GC:  FP00005327 
Title 
A Phase II Study of Photodynamic Therapy (PDT) with Photofrin® (IND 
104,613) for Recurrent High-Grade Gliomas in Adults 
Principal Investigator 
Harry T. Whelan, MD 
Protocol Investigators 
Please refer to page 4 of the protocol. 
Sponsor(s) & 
Collaborators 
Sponsor-Investigator: 
Harry T. Whelan, MD 
Industry Collaborator: Pinnacle Biologics Inc.  
Institution(s) 
Medical College of Wisconsin/Froedtert Hospital 
IND Number(s) 
 
Name of Approved 
Investigational Drug(s)
Hematoporphyrin Derivatives (HPDs) 
Photofrin® (porfimber sodium, 75 mg) for Injection 
Name of Approved 
Investigational 
Devices(s) 
Angiodynamics DIOMED 630 PDT Laser 
Laserscope KTP/532® Surgical Laser System(Series 800) A 
Laserscope KTP YAG® Surgical Laser System (Series 800) A 
 
A Pending FDA Approval 
Dose of Investigational 
Drug 
2.5 mg kg-1 Photofrin® (porfimer sodium, 75 mg) for Injection 
240 J cm-2 Laser light (630 nm) 
Route of 
Administration 
Investigational Drug:  Intravenous Injection (IV), over 3 to 5 minutes 
Photodynamic Therapy:  Intraoperative Photoillumination 
Study Population/ 
Treatment Group(s) 
Single Arm, adult patients with recurrent high-grade gliomas will receive 
one dose of Photofrin® and PDT during the time of clinically indicated 
tumor resection surgery. 
Sample Size 
30 Adult patients  
Selection of Study 
Patients 
30 adult patients with high-grade recurrent gliomas will be referred to 
and/or screened at the MCW/FH Cancer Center.  Patients will be reviewed 
by the Neuro-Oncology Brain Tumor Board and determine if tumor 
resection will be part of their clinically indicated plan of care.  An 
investigative team member and a neuro-oncologist will determine if 
potential patients meet the inclusion and exclusion eligibility criteria as 
defined in the protocol. 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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Page 7 of 78 
Inclusions Eligibility 
Criteria 
1.
Age:  ≥ 18 years 
2. Disease:  Patients with relapsed or refractory high-grade glioma are 
eligible.  Patients must have had histologic verification of malignancy at 
original diagnosis or relapse.  Tumors must be supratentorial in 
location.   
3. Disease Status:  Patients must have potentially resectable disease. 
4. Therapeutic Options:  Patients’ current disease state must be one for 
which there is no known curative therapy or therapy proven to prolong 
survival with an acceptable quality of life. 
5. Performance Level:  Karnofsky ≥ 50%  
Note:  Neurologic deficits in patients with CNS tumors must have been 
relatively stable for at least 7 days prior to study enrollment.  Patients 
who are unable to walk because of paralysis, but who are up in a 
wheelchair, will be considered ambulatory for the purpose of assessing 
the performance score. 
6. Predictable Life Expectancy:  > 8 weeks 
7. Prior Therapy:  Patients must have fully recovered from the acute toxic 
effects of all prior anti–cancer chemotherapy.  At least three weeks from 
previous chemotherapy and 4 weeks from prior radiation therapy 
Note:  Although clinical determination of true progression vs. 
pseudoprogression may be difficult within the first 12 weeks following 
radiation and/or chemotherapy, qualified candidates need only be 4 
weeks out from prior radiation and/or chemotherapy, a common 
standard of other recurrent glioma trials. 
8. Organ Function: 
a. Adequate bone marrow function 
i. Absolute neutrophil count ≥ 1,000 
ii. Platelet count ≥ 100,000 (may transfuse to meet requirement) 
b. Adequate renal function 
i. Creatinine clearance or radioisotope GFR ≥ 70 60 mL/min/1.73 
m2  
c. Adequate liver function 
i. Bilirubin (direct) ≤ 3X upper limit of  normal (ULN) for age 
ii. SGPT (ALT) ≤ 10X ULN 
1. For the purpose of this study, the ULN for SGPT is 45 U/L 
iii. Serum albumin ≥ 2 g/dL 
d. Adequate coagulation 
i. PT and INR ≤ 2X ULN , per institutional guidelines 
9. Central Nervous System Function:  Patients with seizure disorder may 
be enrolled if receiving non– enzyme inducing anticonvulsants and well 
controlled. 
10. Informed Consent:  All patients or legally authorized representatives 
must sign a written informed consent according to institutional 
guidelines. 
11. All available archival tumor tissue slides disease evaluations should be 
reviewed by a Froedtert Health-MCW neuropathologist prior to study 
enrollment. 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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Page 8 of 78 
Exclusion Eligibility 
Criteria 
1.
Disseminated disease 
2. Pregnancy or Breast–Feeding:  Pregnant or breast–feeding women will 
not be entered on this study, as risks of fetal and teratogenic adverse 
effects of Photofrin® are not known. 
3. Other concurrent tumor therapy 
4. Subjects with porphyria 
5. Subjects taking potentially photosensitizing drugs (Appendix 3) 
6. The presence of adverse events of neurologic function, photosensitivity, 
or photophobia Grade 4 or higher (CTCAE Version 4.0)47 
7. Allergy to eggs, soybean oil, or safflower oil (due to potential allergy 
against intralipids) 
8. Patients who in the opinion of the investigator may not be able to 
comply with the safety monitoring requirements of the study are not 
eligible. 
Estimated Length of 
Study 
Patients will be followed up for 3 years following their PDT treatment.  
Accrual Period is projected to take 3 years with an average of 10 patients 
enrolling annually.   
Regimen 
Patients will be give one regimen of the investigational drug for PDT at the 
time of normal tumor resection for recurrent, high-grade gliomas 
Design 
Single Arm, Phase II Study 
Multicenter 
No 
Blinding 
None 
Randomization 
None 
Primary Objective(s) 
1.1.1 
To estimate the six-month relapse-free survival (RFS) distribution 
in adults with recurrent gliomas 
Secondary 
Objective(s) 
1.2.1 
To further explore and report descriptively the safety and 
tolerability of photodynamic therapy (PDT) in adults with recurrent glioma 
tumors 
1.2.2 
To obtain preliminary data toward determining whether this 
combination results in higher remission rate when compared to historical 
data 
1.2.3 
To further explore and report progression-free survival and overall 
survival for three years post PDT treatment 
1.2.4 
To measure complete response, partial response, stable disease or 
progressive disease using the response assessment for Neuro-Oncology 
(RANO) criteria with the follow-up medical imaging, which specifically 
incorporates volumetric measurements of brain tumor enhancement and 
clinical measures of neurological decline and to compare these outcomes to 
historical controls 
Other Outcomes of 
Interest 
None at the time 
 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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PROTOCOL REVISION HISTORY 
 
Version 
No. 
Revision 
Date 
Summary of Changes 
1.0 
01/15/2013
Version of the Original Submission (OS) 
1.1 
05/10/2013
Changes Requested by the MCW/FH IRB, Letter Dated 
11/07/2013 
 
Removed References to Avastin from the protocol  
 
Administrative Changes/Updates 
2.0 
07/14/2014
Protocol Reformatting Overhaul for the Cancer Center CTO 
 
Addition of the following protocol sections: 
 Title page 
 Table of Contents 
 Study Committee page 
 Protocol Synopsis 
 List of Abbreviations 
 7.0 
Investigational Drug and Device Information 
 10.0 
Statistical Considerations 
 11.0 
Evaluation Criteria 
 12.0 
Adverse Event Reporting Requirements 
 13.0 
Study Data Collection and Safety Monitoring 
 14.0 
Conduct of Study 
 Appendix 4 
Overview of Published Literature:  Photodynamic Therapy 
 
Reformatted Sections from Letters (A, B, C,.. etc.) to Numbers (1, 2, 3, … etc.) 
 
Target Accrual updated from 12-18 patients to 30 patients 
2.0 
08/08/2014
Changes Requested by the FRC on 07/22/2014 and 08/04/2014 
Changes Requested by the SRC on 06/16/2014 
 
 
 
Administrative Updates were made to the following sections 
 Section 1.0: 
Reformatted Primary and Secondary Objectives 
 Section 2.6: 
Titles were provide for subsections 2.6.1, 2.6.2, 2.6.3 
 Section 3.4:  
Updated to clarify screening and eligibility process 
 Section 6.7: 
Clarification of use of other investigational agents 
 References:  
Reference numbered 59 to 73 were added 
 
Section 3.2 
 Clarification of Protocol Screening Process to avoid treatment of necrosis 
and/or pseudoprogression 
 
Section 5.7.1 
 Clarification of Study Endpoints, Tests and Procedures 
 
Section 6.2 
 Included specifications for monitoring pulse oximetry 
 
Appendix 1 
 Updates were made to clarify protocol specific procedures, observations, 
and EHR data collection of the patients’ standard of care 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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Page 10 of 78 
Version 
No. 
Revision 
Date 
Summary of Changes 
2.0 
08/29/2014
Changes Requested by the SRC on 08/21/2014 
 
 
 
Section 2.3:
Additional background added to clarify the dose of 
 
 
 
Photofrin® 
 
Section 5.1.1: 
Table of Study Specific Procedures added for  
 
 
 
Clarification 
 
Section 5.1.3: 
Updated to clarify that patients will receive Photofrin® in 
 
 
 
the Adult Translational Research Unit  
 
Section 5.1.6: 
Administrative update for clarification 
 
Section 5.1.7: 
Administrative update to account for the occurrence of 
 
 
 
weekends and holidays 
 
References: : 
Addition of reference number 73 
2.0 
10/30/2014
Addition of Data Safety Monitoring Plan for DSMC Review 
 
 
 
Title page:
Clarification of clinical trial funding and support 
 
Title page:  
Change to MCW/FH IRB protocol number 
 
Table of Contents: 
Administrative updates  
 
Study Committee: 
Administrative updates to Nonemergency Contact 
 
Study Committee: 
Administrative updates to Collaborators Information 
 
Protocol Synopsis:  Update to new MCW/FH IRB protocol number 
 
Protocol Synopsis:  Clarification to Selection of Study Patients 
 
Section 7.1.7: 
Administrative updates to Collaborators Information 
 
Section 12.3:  
Administrative change to section title 
 
Section 12.6.1:  
Clarification provided for Reporting to the MCW/FH  
 
 
 
IRB 
 
Section 12.6.2:  
Clarification provided to guide reader where to look for
 
 
 
expedited reporting to the DSMC 
 
Section 13.3.2:  
Addition/Clarification Expedited Reporting in the Data 
 
 
 
Safety Monitoring Plan 
 
Section 13.3.3:  
Interim Analysis and Stopping Guidelines section added 
 
 
 
to the Data Safety Monitoring Plan 
 
Section 13.3.3:  
Safety Monitoring and Stopping Guidelines section   
 
 
 
added to the Data Safety Monitoring Plan 
 
Section 13.4.1:  
Administrative formatting update 
 
Section 13.4.2:  
Administrative formatting update 
 
Section 13.5:  
Study records will be retained for 10 years per the  
 
 
 
MCW/FH IRB SOP 
2.0 
12/01/2014
Administrative Update for MCW/FH IRB and FDA Review  
 
 
 
Section:
Protocol Revision History Added/Completed 
 
ICF: 
Replaced ‘Clinical Cancer Center’ with ‘Hope Clinic’  
 
ICF: 
Update Information regarding blood clotting risks 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
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Page 11 of 78 
LIST OF ABBREVIATIONS 
 
AE 
 
 
adverse event 
ALT 
 
 
Alanine Aminotransferase 
ANC  
 
absolute neutrophil count 
AST 
 
 
aspartate aminotransferase 
AUC  
 
area under the concentration time curve 
BP 
 
 
blood pressure 
BUN  
 
blood urea nitrogen 
CI 
 
 
confidence interval 
CNS  
 
central nervous system 
 
CR 
 
 
complete remission 
CrCl 
 
 
creatinine clearance calculator 
CRF 
 
 
case report forms 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program 
CTMS  
 
Clinical Trials Management System  
CTO  
 
Clinical Trials Office 
DFS 
 
 
disease free survival 
DLT 
 
 
dose limiting toxicity 
DSMC  
 
data safety monitoring committee 
DSMP  
 
data safety monitoring plan 
ECHO  
 
echocardiogram 
EFS 
 
 
event free survival 
EP 
 
 
European Pharmacopeia 
 
FISH  
 
fluorescence in situ hybridization 
FRC 
 
 
Faculty Review Committee 
GFR  
 
glomerular filtration rate 
HgB 
 
 
hemoglobin 
HpD 
 
 
hematoporphyrin derivative 
HSV  
 
herpes simplex virus 
IRB 
 
 
Institutional Review Board 
LDH  
 
lactate dehydrogenase 
MCW  
 
Medical College of Wisconsin 
MFC  
 
multiparameter flow cytometry 
MRD  
 
minimal residual disease 
MTD  
 
maximum tolerated dose 
MRI 
 
 
magnetic resonance imaging 
MUGA 
 
multi gated acquisition scan 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 12 of 78 
NOS  
 
not otherwise specified 
NRM  
 
non-relapse mortality 
NS 
 
 
normal saline 
OnCore™ 
 
Online Enterprise Research Management Environment 
ORR  
 
overall response rate  
OS 
 
 
overall survival 
PCP 
 
 
pneumocystis carinii pneumonia 
PCR 
 
 
polymerase chain reaction 
PDT 
 
 
photodynamic therapy 
PFS 
 
 
progression free survival 
PI 
 
 
principal investigator 
PR 
 
 
partial response 
PS 
 
 
photosensitizer 
RFS 
 
 
recurrence free survival 
SAE 
 
 
serious adverse event 
SIRS  
 
systemic inflammatory response 
SRC 
 
 
Scientific Review Committee 
ULN  
 
upper limit of normal 
UPIRSO 
 
unanticipated problems involving risks to subjects or others 
USP 
 
 
United States Pharmacopeia 
WBC  
 
white blood count 
 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
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Page 13 of 78 
1.0 
GOALS AND OBJECTIVES/SCIENTIFIC AIMSPrimary Objectives/Aims 
 
1.1.1 To estimate the six month relapse-free survival (RFS) distribution in adults with recurrent 
gliomas 
 
 
1.2 
Secondary Objectives/Aims 
 
1.2.1 To further explore and report descriptively the safety and tolerability of photodynamic 
therapy (PDT) in adults with recurrent glioma tumors 
 
1.2.2 To obtain preliminary data toward determining whether this combination results in higher 
remission rate when compared to historical data 
 
1.2.3 To further explore and report progression-free survival and overall survival for three 
years post PDT treatment 
 
1.2.4 To measure complete response, partial response, stable disease or progressive disease 
using the response assessment for Neuro-Oncology (RANO) criteria with the follow-up 
medical imaging, which specifically incorporates volumetric measurements of brain 
tumor enhancement and clinical measures of neurological decline and to compare these 
outcomes to historical controls 
 
 
 
 


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2.0 
BACKGROUNDIntroduction/Purpose 
 
High-grade gliomas are highly vascular tumors with tendency to infiltrate.  Tumor growth results 
in breakdown of the blood-brain barrier via secretion of vascular endothelial growth factor, 
which simulates angiogenesis and increases endothelial cell permeability.57   Even with standard 
treatment of surgery, radiation and chemotherapy, these tumors almost always recur.  Despite 
extensive research, little advancement has been made in the treatment changing overall survival.  
Treatment challenges exist, given the inherent nature of malignant tumor cells to migrate among 
the normal architecture of the brain, creating an intricate neuronal network.  Even successful 
surgeries as evident by gross total resections are plagued with tumor recurrence nearly 100% of 
the time due to microscopic infiltrative disease.  The presence of the blood-brain barrier limits 
the ability of systemically administered medications in reaching the target of action.   
 
Studies have shown that a majority of malignant gliomas recur within 2 cm of the original tumor 
location and only a small number of patients achieve a long-term survival.53, 54  New therapies to 
reduce local recurrence rate and late morbidities are urgently needed. 
 
 
2.2 
Photodynamic Therapy 
 
Photodynamic therapy (PDT) is a paradigm shift from standard treatment for brain tumors.  The 
principle behind PDT is light-mediated activation of a photosensitizer (PS) that is selectively 
accumulated in tumor cells resulting in tumor cell destruction through singlet oxygen 
production.56 The PS agent is systemically administered and 24 hours later the tumor is 
surgically resected.  Retained PS in tumor cells in the resection cavity is then activated using a 
laser light of appropriate wavelength resulting in tumor cell death.  This approach has been used 
successfully in preclinical models of brain tumors2,5,7 and in a small number of patients including 
some children3,4.  The type of PS agent, the dose of PS and the light source have all shown to 
influence outcomes3,4.  Optimizing the PS agent and laser light combination have not been 
performed and will be important to maximize efficacy and minimize toxicity of this novel 
therapeutic approach41. 
 
 
2.3 
Hematoporphyrin Derivative and Photofrin® 
 
Photofrin® is a second-generation hematoporphyrin derivative (HpD) that is selectively 
accumulated in tumor tissue compared with normal brain in preclinical models32 and in human 
subjects3,4.  Photofrin® targets tumor cells in addition to vascular structures providing a biologic 
advantage over others that primarily target tumor vasculature for disease control.  Importantly, 


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the level of uptake of Photofrin® by normal brain cells in previous studies would be predicted to 
leave normal brain relatively unaffected by the photo-illumination.   
 
A study from Australia using PDT in adult and a few adolescents with high-grade gliomas 
demonstrated 3 year survival overall survival rates of 37-56% 4, much greater than historical 
controls.  Stylli, Kaye and colleagues found that the type of laser for photo-illumination was not 
important to patient outcome.  They did show that higher laser light doses were associated with 
statistically improved long-term survival in patients with primary or recurrent high-grade 
gliomas.  Importantly, their approach was associated with minimal immediate or late toxicities.  
Stylli, Kaye and colleagues used HpD (5 mg kg-1) and Photofrin® (2.5 mg kg-1) as the PS agent4.  
In 1981, Dougherty73 separated HpD by gel exclusion chromatography and identified the 
component of the mixture responsible for the tumor photosensitizing ability.  This component 
represented approximately 45% of the mixture and is the basis for the currently available 
commercial drug Photofrin®.  The Stylli and Kaye et. al group has since revised his protocol to 
use 2.5 mg kg-1 of Photofrin® as the equivalent of the original 5.0 mg kg-1 of HpD (Stanley 
Stylli, MD, e-mail communication, April 2008). 
 
 
2.4 
Significance 
 
Brain and other nervous system cancers affect a substantial number of people, with 22,910 
estimated new cases in the U.S. for the year 2012, and estimated deaths for 2012 of 13,700.8 
Migration of malignant brain tumor cells is a particular problem in the treatment of primary brain 
tumors, as few treatment options are available, and recurrent growth often occurs for most 
malignant tumors.  Ultimately, blocking or controlling the infiltration of these cells may allow 
the prevention or amelioration of brain tumor dispersal.  The development of a treatment that 
targets tumor cells dispersed in the surrounding cellular tissue would be a powerful tool in 
fighting the reoccurrence of brain tumors after primary interventions.  Photodynamic therapy 
(PDT) is one such possible treatment. 
PDT is a cancer treatment modality that involves a localized PS agent, which upon activation 
with light destroys tumors.9-19 This tumor destruction is achieved by a selective retention of the 
PS in tumor cells, effecting cell destruction via the production of singlet oxygen upon localized 
illumination by light set at the appropriate wavelength. 
 
For PDT to work effectively, it must be shown that the PS chosen is taken up by the targeted 
tumor cells in larger quantities than normal cells, and does so when using practical and safe 
dosage levels.  Large molecules are normally prevented from entering the brain by the presence 
of the blood-brain barrier.  An effective PS therefore must be able to pass this barrier, and be 
detected in tumor cells in amounts beyond that attributable to any physical breakdown of this 


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barrier.  Uptake and biodistribution of PS agents such as hematoporphyrin derivative (HpD), its 
major component dihematoporphyrin (DHE), and the second generation HpD derivative 
Photofrin® have been investigated in several studies, using a variety of normal tissues and tumor 
models, and fluorescence, 3H, 14C, and 111In detection.20-32 For our studies, Photofrin® was 
labeled with Indium-111.  Labeling yield of 111In-Photofrin® was > 95%, as determined by 
chromatographic analysis.32 In animal and human studies, the bio-distribution of conjugated 
111In-Photofrin® was determined using external imaging and quantitation with a gamma camera 
(Figure 1).  99mTC-DTPA was used as a control for nonspecific uptake.  Specific tumor uptake of 
the 111In-Photofrin® occurred well beyond that resulting from blood-brain-barrier breakdown.  
Tissue levels of Photofrin® were seven times greater in tumor tissue than in the surrounding 
normal brain tissue, with the greatest concentration occurring at 24 hrs.32 In our initial clinical 
study using doses from 0.75 mg kg−1 to 2.0 mg kg−1, preferential tumor uptake was documented 
in humans.  Overall, our studies indicate7 that there is preferential uptake/retention of Photofrin® 
labeled with 111In in tumor cells as compared to normal cells.  Normal cells, therefore, should be 
relatively unaffected by the photoillumination. 
 
Figure 1: 24 hour image of 111In-labeled Photofrin® before tumor resection.  The pictures 
demonstrate intense uptake of 111In-labeled Photofrin® as shown by the darker areas visible in the 
anteroposterior and lateral views of a patient with an anaplastic ependymoma.3 
 
A number of clinical studies have published updates on the use of HpD-PDT in human brain 
tumors.17,19,34-38 HpD doses range from 2.0 - 10.0 mg kg-1, with fluences ranging from 0.9 - 68 J 
cm-2.  In some studies, fluences are not given, but total radiant energy doses of 658 - 2028 J are 
reported.  Overall, complications of PDT, such as skin photosensitization and cerebral edema, 
are within acceptable limits and many malignant gliomas showed a response to PDT which 
translated into prolonged survival.16 However, these responses do not show the dramatic 
improvement in survival rates seen in the Australian study.4 Development of a treatment protocol 


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matching these survival rates in the U.S. could provide a substantial improvement in domestic 
cancer treatments.  In addition, most of the studies using Photofrin® have been done on adults 
and on supratentorial brain tumors.   
 
 
2.5 
Innovation 
 
Since Photofrin® will preferentially accumulate in tumor cells in quantities beyond that due 
solely to diffusion or break down of the blood-brain barrier; these cells should selectively 
experience destruction upon exposure to light of the appropriate wavelength and of sufficient 
energy.  Light in the near infrared range (NIR) can penetrate some distance through tissue, 
allowing it to reach cells containing PS, and will energize the PS with production of cell 
destructive singlet oxygen.  Specifically, the attenuation depth (defined as 37% loss) in brain 
tissue, with 1.5 W of red light available, has been measured in vivo in the range of 2–4 mm,19 
with effective tumor necrosis to three times this distance.39 With light generated at up to 2W the 
Multidiode PDT 4G laser available from Intermedic (Intermedic Arfran S.A., Spain), necrosis of 
tumor cells at a depth of 2 cm or beyond is not unreasonable.  The majority of high-grade 
gliomas recurs within 2 cm of the original tumor location.40 Photo-illumination commencing at 
the center of the tumor resection cavity, and falling on the tissue nearest the original tumor, 
should penetrate far enough into the tissue to reach tumor cells that have migrated away from the 
original site.  In this manner, it is hoped to destroy any migrating brain tumor cells within 2 cm 
from the original tumor location, without harming the healthy cells in which they are dispersed. 
 
The excellent results of the Australian group were obtained with a 4 W KTP laser.4  The 
Multidiode PDT 4G laser is able to deliver the light at the power levels needed for effective 
tumor cell destruction.  If we were to choose to use a much weaker light source than this, we 
would give the tumor cells a much better chance to repair photodynamic damage.  As a result, 
we could end up with much reduced anti-tumor effect, even if we prolonged illumination times 
to compensate for the low fluence rate of the other light sources.  In other words, photodynamic 
damage needs to be delivered at a rate that overwhelms tumor cell repair mechanisms.  Optimal 
light and PS dosing regimens are necessary for effective PDT treatment of glioma patients.  Up 
to now, light and PS dosing regimens have proven to be less than optimal, and there is need for 
further work in this area to optimize results.41 
 
The use of the Multidiode PDT 4G laser to activate PDT agents in a short period of time also 
enhances patient safety.  PDT will be delivered to the cavity left following tumor resection.  
Since patients will already be under general anesthesia for several hours for the preceding 
resection procedure, shortening the duration of the subsequent PDT stage, which may last up to 
45 minutes, will certainly be advantageous. 


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2.6 
Relevant Clinical Data 
 
2.6.1 Photoillumination and Postoperative Intracranial Pressure 
Muller and Wilson have reported that using photoillumination of the tumor cavity had increased 
intracranial pressure in the immediate postoperative period, but this was easily controlled with 
steroid therapy.16,19 The PS used was either HpD or DHE, and fluences were 8-175 J cm-1.  As 
patients will typically be on steroid therapy, we do not anticipate problems with increased 
intracranial pressure; we will be paying special attention however to any increased steroid 
requirements.  Muller also reported on 50 cases of malignant glioma treated with cavitary 
photoillumination and suggested that greater light doses resulted in increased survival.16 
 
2.6.2 PDT Laser Light Dosing 
Powers et al.36 recently reported the results of 7 patients with recurrent gliomas treated with 
stereo tactically implanted optical fibers.  Two of the 7 patients remained free of tumor more 
than 15 months after treatment.  However, the other 5 patients had tumor recurrence within 2 
months of their treatment that appeared at the border of the PDT-induced area of tumor necrosis 
and was located in the brain adjacent to tumor (BAT) medially adjacent to the solid tumor.  
Photofrin® levels were measured from surgical tissue specimens in all patients and showed 
adequate levels of PS in tumor and BAT for photosensitization.  From this study it was 
concluded that tumor recurrence occurs as a result of insufficient light dose (658-2028 J) to the 
BAT and lack of photosensitization of tumor cells invading this region.  These reports show the 
necessity for increased PS levels and greater light doses for activation in order to improve 
outcomes.   
 
2.6.3 Stylli and Kaye et. al.:  PDT 3 Year Survival Analysis 
Clinical studies by Stylli and Kaye et al. 4 report on hematoporphyrin derivative (HpD) 
mediated–PDT that had been investigated as an adjuvant treatment for cerebral high- g r a d e  
glioma.  The study recorded the survival of patients at the Royal Melbourne Hospital, 
utilizing the Victorian Cancer Registry database for patients treated with adjuvant PDT 
following surgical resection of the tumor.  For primary (newly diagnosed) tumors, median 
survival from initial diagnosis was 76.5 months for anaplastic astrocytoma (AA) and 14.3 
months for glioblastoma multiforme (GBM).  73% of patients with AA and 25% with GBM 
survived longer than 36 months.  For recurrent tumors, median survival from the time of 
surgery was 66.6 months for AA and 13.5 months for GBM.  57% of patients with recurrent 
AA and 37% of patients with recurrent GBM survived longer than 36 months.  Younger 
patients (< 40) had even better survival.  These survival data for high–grade glioma patients 
are superior to the current published survival rates in adult as well as pediatric studies.  Laser 
light doses above the sample median of 230 J cm–2 were associated with better prognosis in 
the 136 patients studied.  There was no mortality directly associated with the therapy; three 


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patients had increased cerebral edema thought to be related to PDT that was controlled with 
conventional therapies.  No patients had permanent neurological deficit.  Of the 29 patients who 
received chemotherapy, no association between the use of chemotherapy and prognosis 
following PDT was found. 
 
2.6.4 Previous Phase 1 Clinical Data 
We conducted a human brain tumor PDT study in 2004 that evaluated the toxicity of PDT 
based on both light– emitting diode (LED) and laser technology in selected patients with 
brain tumors 3.  Complete results are presented below in Table 1. 
 
Table 1:  Patient characteristic and tumor location in relation to PDT– exposed eloquent brain 
regions 3 
PT Age 
(Yrs.)
Location of 
Tumor 
Histology 
Eloquency 
Photosensitizer 
Light Source 
Neurotoxicity 
Relapse Free
Survival 
1
14 
Right 
parietal 
Anaplastic 
ependymoma 
Visual cortex
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
11 months 
(treatment 
one) 
 
16 
Right parietal Ependymoma 
Visual cortex
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
3 months 
(treatment 
two) 
 
20 
Left occipital Ependymoma 
 
Photofrin® 
2.0 mg kg–1 
LED – balloon 
None 
9 months 
(treatment 
three) 
2
21 
Right 
temporal 
Anaplastic 
oligoastrocytoma 
Cerebral 
peduncle  
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
7 years 
7 months 
(to date) 
3
36 
Left frontal 
Anaplastic 
oligoastrocytoma 
None 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
1 year 
5 months 
4
17 
Right frontal Medulloblastoma 
Thalamus 
Photofrin® 
2.0 mg kg–1 
Laser – fiber 
None 
10 months 
5
14 
Right frontal 
lobe 
Central 
neuroblastoma 
Speech 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
8 weeks 
6
1 
Left parietal 
Rhabdoid tumor 
Speech 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
10 weeks 
7
19 
Cerebellar 
vermis 
Anaplastic 
astrocytoma 
Floor of the 
4th ventricle 
Photofrin® 
2.0 mg kg–1 
Laser – fiber 
severe truncal ataxia, 
bilateral facial 
weakness, dysphagia 
3 years 
10 months 
8
48 
Right occipital Glioblastoma 
multiforme 
Visual cortex
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
9 months 
9
1 
4th ventricle 
Ependymoma 
Floor of the 
4th  ventricle 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
4 months 
10
51 
Left frontal 
Anaplastic 
oligoastrocytoma 
None 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
3 months 


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PT Age 
(Yrs.)
Location of 
Tumor 
Histology 
Eloquency 
Photosensitizer 
Light Source 
Neurotoxicity 
Relapse Free
Survival 
11
45 
Right 
temporal 
Glioblastoma 
multiforme 
Cerebral 
peduncle 
Photofrin® 
2.0 mg kg–1 
Laser – balloon right facial nerve palsy 6 months 
12
11 
Brain stem & 
Left 
cerebellum 
Pilocytic 
astrocytoma 
Infratentorial
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
6 months 
13
12 
Right frontal Central 
neuroblastoma 
None 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
4 years 
5 months 
(to date) 
14
39 
Right frontal Astrocytoma 
None 
Photofrin® 
2.0 mg kg–1 
Laser – balloon 
None 
4 years 
(to date) 
15
20 
Left frontal 
Glioblastoma 
multiforme 
None 
Photofrin® 
2.0 mg kg–1 
LED – balloon 
None 
4 months 
16
18 
Brain stem 
Astrocytoma 
Infratentorial, 
med. oblong.
Photofrin® 
2.0 mg kg–1 
LED – balloon 
None 
2 months 
17
15 
Right 
temporal 
Glioblastoma 
multiforme 
Cerebral 
peduncle 
Photofrin® 
2.0 mg kg–1 
LED – balloon 
None 
2.5 months 
18
51 
Left posterior 
frontal 
Glioblastoma 
multiforme 
Motor cortex
Photofrin® 
2.0 mg kg–1 
LED – balloon 
None 
2 months 
19
59 
Right 
temporal 
Adenocarcinoma 
None 
BPD 
0.25 mg kg–1 
LED – balloon 
None 
5 months 
20
53 
Left front 
temporal
Malignant 
meningioma
Speech 
BPD 
0.25 mg kg–1
LED – balloon 
None 
5 months 
 
Twenty patients (eight pediatric) with recurrent malignant brain tumors received 22 treatments 
with PDT and Photofrin® or Visudyn®.  Sixteen tumors were supratentorial and four tumors 
were infratentorial.  Eighteen patients received IV Photofrin® 24 hours prior to light exposure 
starting at 0.75 mg kg–1.  Two patients received LED light with 0.25 mg kg–1 of Visudyne®, a 
benzoporphyrin derivative (BPD, QLT, Vancouver, BC, Canada).  Laser and LED arrays were 
used to deliver 100 J cm–2 of light to the sensitized tumors.  Of the 22 PDT treatments, 15 
treatments were performed with laser (13 by balloon adapter and two by fiber optic with 1.5 cm 
cylinder diffuser tip) and seven treatments by LED using a balloon adapter.  At the maximum 
Photofrin® dose of 2.0 mg kg–1 five patients received laser–balloon adapter light exposure and 
five patients received LED light.  Quantitative analysis of toxicity and time to progression was 
performed. 
 
Only two patients displayed neurotoxicity, one after laser treatment using an interstitial fiber 
directly inserted into the tumor, and one with the laser–balloon adapter combination.  
Escalating doses of Photofrin® were tolerated to the maximum dose of 2.0 mg kg–1.  PDT in 
the posterior fossa or near eloquent brain was tolerated using the LED or laser–balloon adapter.  


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All patients had tumor responses as documented by MRI scan and the mean time to tumor 
progression after PDT was 67 weeks. 
 
Eight of the patients were pediatric patients, all of whom received Photofrin®, who 
exhibited relapse–free survival times ranging from 8 weeks to 4 years 5 months (to date as of 
publication of the study) with a mean value of 12.6 months.  None showed neurotoxicity.  Of 
the 20 patients, four had tumors in the posterior fossa area, with one developing a significant 
neurological deficit.  This patient was one of the two using interstitial fiber illumination. 
 
The pediatric patients did not have any photosensitivity.  Only one adult in the study had 
photosensitivity due to the use of the fiber optic involving the cerebellar peduncle near the 
brain stem and this was because the fiber optic catheter was next to brain tissue.  None of the 
patients had any skin or eye photosensitivity. 
 
This pilot data shows that PDT with LED or laser balloon–adapters (also tunable dye laser) 
has acceptable toxicity in brain tumor patients, and can be successfully used in both 
pediatric patients and in those with infratentorial tumors. 
 
2.6.5 Pediatric Phase I Clinical Data 
The pediatric phase I study CHW 13-31 is a dose–escalation study of Photofrin® in pediatric and 
adolescent patients with recurrent or refractory brain tumors.  The primary objectives of this 
study are to identify a maximum tolerated dose (MTD) or recommended Phase 2 dose 
(RP2D) and characterize the toxicity profile of Photofrin® in pediatric and adolescent patients 
with recurrent/refractory brain tumors. 
 
Patients ranging in age from 6 months to 18 years with recurrent/refractory brain tumors will be 
eligible.  Supratentorial and infratentorial (posterior fossa) brain tumors that are potentially 
resectable are eligible.  Diagnoses include PNET (primitive neuro–ectodermal tumor), 
medulloblastoma, ependymoma, high–grade glioma, germ–cell tumor, and/or ATRT (atypical 
teratoid/rhabdoid tumor).  Disease evaluation will be completed after completion of PDT, and at 
1, 3, 6, 9, 12, 18, 24, 30 and 36 months thereafter.  Dosing of Photofrin® will be based on body 
weight (kg).  The trial started with a dose of 0.5 mg kg-1.  At this does level three patients were 
enrolled and there were no dose limiting toxicities (DLTs).  (Phase I Dose Level 1 Toxicity 
Review Study Progress Report, December 2013)  Doses will be escalated to 1.3 mg kg–1, 2 mg 
kg–1 and 3 mg kg–1 in subsequent cohorts using a rolling three design 50.  The trial is currently 
open and accruing. 
 
2.6.6 Correlative Nonclinical Studies 
In addition to the 2004 clinical trial discussed above, our team has performed studies in PDT 


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using a canine glioma model, both in vivo and in vitro, 2, 6, 7 and human glioma cells in vitro 5, 
7.  Also studied were radiolabeled PS uptake, 3, 7, 32 and alternate light sources and PS choices 3, 
5–7.  This work provides a depth of background and experience encompassing nearly 20 years. 
 
 
2.7 
Rationale For The Adult Phase II Study 
 
The survival of adult patients with recurrent brain tumors is measured in months with few long-
term survivors.  The methodology utilized by Stylli, Kaye and colleagues has shown impressive 
survival rates in adults and adolescents with high–grade gliomas with minimal acute or late 
toxicities.  We believe the demonstrated efficacy and safety profile of the Stylli and Kaye 
methodology in adults warrants further study with recurrent/refractory high-grade gliomas.  
Medical College of Wisconsin is one of the few centers in the country with experience utilizing 
PDT technology for the treatment of brain tumors.4  As a result we are uniquely poised to apply 
the methods used by Stylli, Kaye and colleagues.  In addition, we also believe that we can further 
improve their encouraging results by partaking in a Phase II trial with Photofrin® at set dose of 
2.5 mg/kg body weight and set light dose of 240 J cm-2 with wavelength at 630 nm.   
 
 
 
 


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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
 
3.1 
Regulatory IRB Approval 
 
All institutional and FDA requirements for human studies must be met.  Local IRB approval of 
this study must be obtained by a site prior to enrolling patients.  Sites must submit IRB 
continuing review and amendment approvals to the sponsor-investigator. 
 
 
3.2 
Patient Screening Process and Eligibility Assessment 
 
3.2.1 Neuro-Oncology Tumor Board Patient Assessment 
Potentially eligible patients will be screened by the Neuro-oncology Tumor Board, which is a 
group of MCW Neurosurgeons, Neuro-oncologists, a Pathologist, and a Radiologist.  This group 
meets on a weekly basis to review cases.  The team’s review of the medical history, laboratory, 
pathology, and imaging results for each case is part of the standard clinical practice.  Indication 
for tumor resection will be determined by evaluating all available imaging studies.  This includes 
variety of specialized MRIs, which are completed on a case-by-case basis with prior insurance 
approval.  If there is not enough evidence to reasonably rule out false positive MRIs, or 
pseudoprogression by the Neuro-oncology Tumor Board, the patient will not meet eligibility 
criteria.  This is because patients must be clinically indicated for gross tumor resection as part of 
their standard of care plan for their disease status.  Refer to Section 4. 
 
3.2.2. PDT Protocol Specific Eligibility Assessment 
An Investigator member of the study team and neuro-oncologist will screen and approve patient 
eligibility specifically for this protocol.  The Screening and Eligibility Check List Case Report 
Form must be prepared by a member of the study team and signed by an investigator member of 
the study team.  A copy of this documentation will be sent to the TRU Nurse to verify prior the 
administration of Photofrin®.   
 
 
3.3 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved consent to review.  The 
investigator or designee will explain all aspects of the study in lay language and answer all 
questions regarding the study.  If the participant decides to participate in the study, he/she will be 
asked to sign and date the consent document.  Patients who refuse to participate or who withdraw 
from the study will be treated without prejudice. 


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3.4 
Patient Registration 
 
After completion of the screening evaluation, an investigator member of the study team will 
document inclusion and exclusion eligibility confirmation.  Written informed consent must be 
obtained prior to patient registration.  Eligible patients will be registered by the Cancer Center 
Clinical Trials Office (CTO) using OnCore™ Clinical Trials Management System (CTMS).   
 
 
3.5 
Patients Who Do Not Begin Study Treatment 
 
If a patient is registered on the study, and is later found not able to begin the planned study 
treatment, for whatever reason, the patient will be removed from study and treated at the 
physician’s discretion.  Study data will be collected until the time of study removal.  The reason 
for removal from study will be clearly indicated on the case report forms. 
 
If a patient begins treatment, and then is discontinued for whatever reason, the patient must be 
followed for 3 months for toxicity review. 
 
 


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4.0 
PATIENT ELIGIBILITY 
 
All clinical, imaging and laboratory studies to determine eligibility must be performed within 
30 days prior to enrollment. 
 
The eligibility criteria listed below are interpreted literally and cannot be waived.  
All clinical and laboratory data required for determining eligibility of a patient enrolled 
on this trial must be available in the patient’s medical or research record, which will serve 
as the source document for verification. 
 
 
4.1 
Inclusion Eligibility Criteria 
 
1. Age:  ≥ 18 years 
2. Disease:  Patients with relapsed or refractory high-grade glioma are eligible.  Patients must 
have had histologic verification of malignancy at original diagnosis or relapse.  Tumors 
must be supratentorial in location.   
3. Disease Status:  Patients must have potentially resectable disease. 
4. Therapeutic Options:  Patients’ current disease state must be one for which there is no 
known curative therapy or therapy proven to prolong survival with an acceptable quality of 
life. 
5. Performance Level:  Karnofsky Score ≥ 50%.   
Note:  Neurologic deficits in patients with CNS tumors must have been 
relatively stable for at least 7 days prior to study enrollment.  Patients who 
are unable to walk because of paralysis, but who are up in a wheelchair, will 
be considered ambulatory for the purpose of assessing the performance 
score. 
6. Predictable Life Expectancy:  > 8 weeks 
7. Prior Therapy:  Patients must have fully recovered from the acute toxic effects of all prior 
anti–cancer chemotherapy.  At least three weeks from previous chemotherapy and 4 weeks 
from prior radiation therapy 
Note:  Although clinical determination of true progression vs. pseudoprogression 
may be difficult within the first 12 weeks following radiation and/or chemotherapy, 
qualified candidates need only be 4 weeks out from prior radiation and/or 
chemotherapy, a common standard of other recurrent glioma trials. 
8. Organ Function: 
a. Adequate bone marrow function 
i. Absolute neutrophil count ≥ 1,000 
ii. Platelet count ≥ 100,000 (may transfuse to meet requirement) 
b. Adequate renal function 


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i. Creatinine clearance or radioisotope GFR ≥ 6070 mL/min/1.73 m2  
c. Adequate liver function 
i. Bilirubin (direct) ≤ 3X upper limit of  normal (ULN) for age 
ii. SGPT (ALT) ≤ 10X ULN 
1. For the purpose of this study, the ULN for SGPT is 45 U/L 
iii. Serum albumin ≥ 2 g/dL 
d. Adequate coagulation 
i. PT and INR ≤ 2X ULN , per institutional guidelines 
9. Central Nervous System Function:  Patients with seizure disorder may be enrolled if 
receiving non– enzyme inducing anticonvulsants and well controlled. 
10. Informed Consent:  All patients or legally authorized representatives must sign a 
written informed consent according to institutional guidelines. 
11. All available archival tumor tissue slides disease evaluations should be reviewed by a 
Froedtert Health-MCW neuropathologist prior to study enrollment. 
 
 
4.2 
Exclusion Eligibility Criteria  
 
1. Disseminated disease 
2. Pregnancy or Breast–Feeding:  Pregnant or breast–feeding women will not be entered 
on this study, as risks of fetal and teratogenic adverse effects of Photofrin® are not 
known. 
3. Other concurrent tumor therapy 
4. Subjects with porphyria 
5. Subjects taking potentially photosensitizing drugs (Appendix 3) 
6. The presence of adverse events of neurologic function, photosensitivity, or 
photophobia Grade 4 or higher (CTCAE Version 4.0)47 
7. Allergy to eggs, soybean oil, or safflower oil (due to potential allergy against intralipids) 
8. Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible. 
 
 
 


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5.0 
TREATMENT PLAN 
 
 
5.1 
Overview of the Treatment Plan 
 
5.1.1 Study Procedures 
The study specific procedures include infusion of Photofrin® intra–operative laser activation of 
Photofrin®, 4 weekly history and physical assessments for toxicity review, and 2 week lab 
assessments for toxicity review.  A table has been provide below for your reference.  All other 
testing including laboratory, radiology as well as the schedule for follow–up will be performed 
as part of standard of care for patients with brain tumors undergoing therapy. 
 
Study Specific Procedures 
Study Calendar 
Time Frame 
Requires A Study 
Specific Hospital Visit? 
Informed Consent 
Before Day 0 
No 
PDT Protocol Specific Screening & 
Eligibility Assessment 
Day -30 to Day 0
No 
HIPAA for Medical Record Follow-Up 
Before Week +5 
No 
Preoperative Administration of Photofrin®
Day 0 
Yes 
Intraoperative Photodynamic Therapy 
Photoillumination 
Day 1 
No 
History and Physical Assessments for 
Toxicity Review 
1st Month 
Follow-up 
No 
Lab Assessments for Toxicity Review 
 Complete blood count 
 Renal function studies (BUN, 
creatinine) 
 Hepatic function studies (ALT, AST, T 
bilirubin, alkaline phosphatase) 
2 Week 
Postoperative 
Assessment 
No 
Medical Record Review & Prospective 
Follow-up* 
Up to 3 Years 
Post PDT 
No 
• A complete of Assessments collected from your medical record for this study is 
delineated in Appendix 1. 
 
 
5.1.2 Pre–Treatment Evaluation (Evaluation Table Appendix 1) 
These must be obtained within 30 days of enrollment. 
1. Complete history and physical examination (including a skin exam) 
2. Karnofsky functional status 


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3. Complete neurological examination including visual acuity when possible 
4. Laboratory assessment: 
a. Complete blood count 
b. Renal function studies (BUN, creatinine) 
c. Hepatic function studies (ALT, AST, T bilirubin, alkaline phosphatase) 
d. Endocrine function studies (TSH, Free T4, IGF–1, IGF–BP3, cortisol) as 
clinically warranted 
5. MRI scan of the brain 
6. MRI scan of the spine, only if clinically warranted 
 
5.1.3 
Preoperative Administration of Photofrin® 
The subjects entering the study will receive a prescribed dose of 2.5 mg kg–1 of Photofrin® 
(supplied by Pinnacle Biologics, Inc., Bannockburn, IL),  given intravenously over 3-5 minutes 
during an outpatient clinic visit, scheduled 24 hours prior to the planned surgical resection.  
Research participants will report to the Adult Translatoinal Research Unit (TRU) to receive the 
injection by a TRU nurse.  Prior to the administration of Photofrin® the TRU nurse will assess 
the patient and ensure the patient has adequate protective gear and clothing for the patient’s 
journey home and back to the hospital for tumor resection the following day.  Subjects will have 
already received a PDT Patient Kit and instructions for protection from sunlight.  Subjects will 
be advised to remain out of direct sunlight and bright artificial lighting for at least 30 days 
and up to 90 days after Photofrin® injection and PDT.  (Appendix 2)  If a photosensitivity 
reaction occurs, subjects are instructed to contact their physician immediately for guidance in 
the treatment of the reaction. 
 
5.1.4 Surgical Treatment for Tumors – Craniotomy and Resection 
Craniotomy and tumor resection will be carried out in the standard fashion in order to achieve 
the maximum tumor resection compatible with preservation of neurological function. 
 
5.1.5 Operative Treatment and Intraoperative PDT of the Tumor 
After tumor resection, room temperature Intralipid (Fresineus Kabi) will be infused into the 
open craniotomy and maintained for approximately 45-90 minutes, while PDT will be 
performed.  The rational for the time frame listed includes the time it would take to drape the 
photosensitive patient, calibrate the optical fiber(s) verify the dose calculations, place the optical 
fibers in the tumor cavity, administer PDT laser light dose of 240 J cm-2, and remove the optical 
fiber(s).  All efforts will be made to minimize additional time in the OR.  Up to a combination of 
2 lasers may be used to supply the prescribed light dose of 240 J cm-2. 
 
The Intralipid will diffuse the light and ensure uniformity of light delivery, and will be 
replenished as needed at the discretion of the surgeon.  The temperature of the tumor cavity can 


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be monitored by use of the Licox probe and should be maintained at normal body temperature 
(37°C). 
 
Photoactivation of Photofrin® is controlled by the total light dose delivered over the treatment 
time.  PDT lasers are equipped with a calibration unit to calibrate the fibers and yield the 
required power density output (mW) necessary to deliver a light dose of 240 J cm–2.  The 
illumination time will be calculated from the power density (mW) emitted by the laser through 
the fiber, and the radius (r) of the resection cavity to deliver a total light dose (energy) of 240 J 
cm–2 at a wavelength of 630 ± 3 nm using the following formula: 
 
Treatment Time (sec) = Light Dose (J cm–2) × Cavity Surface (cm2) × 1000 
Power Density (mW) 
 
Where, Cavity Surface (cm2) = 4⋅π⋅ r2 
 
The optic fiber or fibers output will be calibrated to the appropriate power density setting using 
the FDA approved laser calibration unit or units according to the procedure described in the laser 
manufacturer’s instructions, or using a suitable external calibration unit. 
 
The subject's head will be positioned on the operating table such that the tumor resection 
cavity is uppermost.  The optical fiber will be placed in the approximate center of the 
surgical cavity and photoillumination will commence.  The laser light exposure time will be 
calculated as above.  An optic fiber probe may be used at the time of photoillumination to 
measure the light flux in the brain or brain tumor in order to ensure that no fall off of light 
penetration into the cavity surface occurs during treatment. 
 
After PDT, the intralipid solution will be removed and the wound will be closed.  The subject 
will be extubated, recovered from anesthesia, and then sent to the intensive care area for 
appropriate observation. 
 
5.1.6 Acute Postoperative Care 
1. When clinically indicated, subjects will be monitored in the Neurosurgical Intensive Care 
Unit for approximately 72 hours postoperatively or as long as deemed clinically 
appropriate by the care team. 
2. When clinically indicated, subjects will have continuous intracranial pressure monitoring 
for approximately 48 postoperative hours or as long as deemed clinically appropriate. 
3. When clinically indicated, subjects will receive postoperative dexamethasone at a dose 


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and for a time period dictated by their clinical condition.  The dose and duration steroid 
administration will be recorded. 
4. Subjects will receive anticonvulsants as deemed clinically appropriate. 
5. Subjects will get an MRI of the resection site 1–3 days following PDT to assess the 
degree of resection 
6. Subjects will receive any additional laboratory and imaging evaluations as clinically 
indicated. 
7. Subjects will continue to be reminded and educated regarding PDT, the precautions in 
place to prevent phototoxicities by minimizing exposure to intense light and avoiding 
other phototoxic medications. 
 
 
5.1.7 Follow–Up 
 Required Standard of Care MRI Evaluations:  Patients will have a post-operative 
MRI of brain on Day +2 (± 1 day), 1st-Month/Week +4 (± 3 days)follow-up, and 6-
Month/Week +24 follow-up with and without gadolinium pending scan results, patient’s 
clinical exam and healing of incision site.   
 First Month:  Patient will be followed in the neurosciences clinic at Froedtert 
Health-MCW Cancer Care Center for a minimum of once a week for four weeks 
following PDT as part of their postoperative standard of care for brain tumor resection.  
During these clinic visits, patients will have a history and physical exam including 
thorough neurological exam and documentation of medicines and doses administered.  
Interval history and physical exams will focus on identifying toxicities related to 
Photofrin® or the PDT procedure.  Additional laboratory and imaging studies will be 
performed as clinically indicated.   
 After the First Month:  Many study participants will go on to receive additional anti-
cancer therapy following recovery of neurosurgery during this time.  Therapy dosing and 
schedule will also be recorded for study purposes as outlined in this protocol.  Patients 
will be followed at a schedule to be determined by their respective treating physicians.  
For study purposes and as part of their routine care, patients will be evaluated from 
Week +1 to Year +3, as clinically indicated, without study specific follow-up time 
points.  During this time, the study coordinator will report survival status when 
required for DSMC review, study progress reports, as well as FDA and IRB annual 
reports.  This is outlined in Appendix 1.  Evaluation will include a thorough history 
and physical, MRI of the resection area, medications and doses and laboratory 
evaluations deemed clinically appropriate.   
 
 
 


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5.2 
Concomitant Therapy Restrictions 
 
5.2.1 Concomitant Medications 
Subjects should not receive other photsensitizing drugs while on protocol therapy or in toxicity 
review.  Appendix 3 lists the commonly prescribed drugs that are known photosensitizers.  
Subjects must use precaution if receiving potentially photosensitizing drugs for the first three 
months following administration of Photofrin®.  The patient and family will be instructed to call 
the Phase II team prior to starting any new medications in the first three months (until Week + 
13, of Day + 90) after Photofrin® administration. 
 
5.2.2 Post PDT Anticancer Therapy 
Many of these patients will receive additional therapy for their recurrent cancer.  Therapy 
dosing and schedule must be recorded for study purposes.  Patients may begin other anticancer 
therapy regimens as early 1 month after PDT.  Anticancer therapy starting before 3 months (90 
days) after PDT should proceed with caution if the regimen contains any possible phototoxic 
agents.   
 
 
5.3 
Modifications For Toxicities 
 
There will be no dose modifications for the administration of Photofrin®.  All enrolled patients 
will receive 2.5 mg kg-1.  If the enrolled patient does not receive the full investigation drug dose 
or complete the intraoperative photodynamic therapy for any reason, the patient should be 
evaluated for toxicities for 90 days.  The patient must follow the precautions and consideration of 
Photofrin® risks. 
 
 
 
 


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6.0 
SUPPORTIVE CARE GUIDELINES AND OTHER CONCOMITANT THERAPY 
 
 
6.1 
Standard Surgical Risks 
 
Supportive care and treatment for reported operative and postoperative adverse events associated 
with standard care craniotomy and resection will be given as appropriate to each patient (anti-
emetics, antibiotics, transfusions, oxygen therapy, nutritional support, palliative treatment for 
pain etc.) according to institutional guidelines.   
 
A. General postoperative complications 
1. Reversal agents for anesthetic complications—as needed if a preoperative level of 
consciousness is not obtained 
2. Respiratory complications 
a. Decreased level of consciousness and inability to protect airway following 
surgery 
b. Development of edema in and around the brain stem 
3. Cardiovascular complications 
a. Hypovolemic shock  
b. Blood pressure—usually normotensive state is maintained 
c. Cardiac arrhythmias 
4. Gastrointestinal complications—gastric stress ulceration and hemorrhage 
5. Endocrine complications 
a. Diabetes insipidus 
b. Syndrome of inappropriate antidiuretic hormone (SIADH) 
c. Cerebral salt wasting 
6. Infectious complications 
a. Meningitis 
b. Brain abscess 
c. Intracranial epidural abscesses 
7. Hematological complications 
a. Deep vein thrombosis (DVT) 
8. Pain 
 
B.  Specific neurologic complications 
1. Hemorrhage 
2. Increased intracranial pressure 
3. Peritumoral edema 
4. Cerebral infarction 


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5. Pneumocephalus 
6. Hydrocephalus 
7. Seizures 
8. Cerebrospinal fluid leak 
9. Cranial nerve deficits 
10. Wound infection 
 
 
6.2 
Supportive Care for Intraoperative PDT Risks 
 
Increased surgical risk due to the PDT procedure is expected to be minimal, as the subject will be 
undergoing a standard care tumor resection. 
 
6.2.1 Photoillumination of the Tumor Resection Cavity 
The addition of an illumination stage results in minor additional risk limited to increased 
temperature due to light energy.  An Intralipid bath will be utilized to control for this possibility.  
Intralipid has micron-sized lipid droplets that efficiently scatter the light.  By placing the distal 
end of the laser fiberoptic directly in this lipid droplet suspension the 630 nm laser light is evenly 
distributed within the tumor resection cavity, thus activating Photofrin® evenly over the entire 
exposed tumor inner surface area.  This reduces risk of any areas of over- or under-exposure to 
light, controlling the photodynamic effect, and avoiding "spotty" overdose or under-dose.   
 
6.2.2 Intraoperative Photosensitivity Precautions 
Reduced light settings and patient draping will be used to avoid potential problems from bright 
surgical lights, whenever possible.  In addition, measuring oxygen saturation with pulse oximetry 
(pulse ox) exposes the skin to red light, which may cause skin burns if left in one place too long.  
When a pulse ox is used during neurosurgery, acute postoperative care and after approximately 
30 days have elapsed (or as long as photosensitivity is experienced), care should be taken to have 
the photo detector/sensor device moved to a new location every few minutes.  Use different 
fingers and toes if necessary.  Continuous monitoring can carried out by setting up multiple 
monitors and rotating on and off status of the fixed sensors, or by moving a single sensor to 
different pulsating arteriolar bed, such as the finger, great toe, nose, or earlobe.   
 
 
6.3 
Photofrin® Risks and Guidelines 
 
6.3.1 Photosensitivity 
The major risk of Photofrin® skin photosensitivity sensitivity, which will persist for some time 
after the procedure.  Risks of photosensitivity can be avoided by taking light exposure 


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precautions.  As such, all patients who receive Photofrin® will be instructed to avoid exposure of 
skin and eyes to direct sunlight or bright indoor light (from examination lamps, including dental 
lamps, operating room lamps, un-shaded light bulbs at close proximity, etc.) for at least 30 days.  
Some patients may remain photosensitive for up to 90 days or more.  The photosensitivity is due 
to residual drug, which will be present in all parts of the skin.  
 
6.3.2 Ocular Sensitivity   
Ocular sensitivity to sun, bright lights, or car headlights, causing ocular discomfort, can occur in 
patients who receive Photofrin®.  For at least 30 days and until ocular sensitivity resolves, 
patients will be instructed, to wear dark sunglasses when outdoors.  Sunglasses have an average 
white light transmittance of < 4% and will reduce risk of ocular sensitivity. 
 
6.3.3 Photobleaching Precautions 
Exposure of the skin to ambient indoor light is, however, beneficial because the remaining drug 
will be inactivated gradually and safely through a photobleaching reaction.  Therefore, patients 
should not stay in a darkened room during this period and should be encouraged to expose their 
skin to ambient indoor light.  The level of photosensitivity will vary for different areas of the 
body, depending on the extent of previous exposure to light.  Before exposing any area of skin to 
direct sunlight or bright indoor light, the patient should test it for residual photosensitivity.  A 
small area of skin should be exposed to sunlight for 10 minutes.  If no photosensitivity reaction 
(erythema, edema, blistering) occurs within 24 hours, the patient can gradually resume normal 
outdoor activities, initially continuing to exercise caution and gradually allowing increased 
exposure.  If some photosensitivity reaction occurs with the limited skin test, the patient should 
continue precautions for another 2 weeks before retesting.  The tissue around the eyes may be 
more sensitive, and therefore, it is not recommended that the face be used for testing.  If patients 
travel to a different geographical area with greater sunshine, they should retest their level of 
photosensitivity.  Conventional ultraviolet (UV) sunscreens will only protect against UV light-
related photosensitivity and will be of no value in protecting against induced photosensitivity 
reactions caused by visible light.  
 
6.3.4 Use Before or After Radiotherapy 
If PDT is to be used before or after radiotherapy, sufficient time should be allotted between the 
two therapies to ensure that the inflammatory response produced by the first treatment has 
subsided before commencing the second treatment.  The inflammatory response from PDT will 
depend on tumor size and extent of surrounding normal tissue that receives light.  It is 
recommended that 2 to 4 weeks be allowed after PDT before commencing radiotherapy.  
Similarly, if PDT is to be given after radiotherapy, the acute inflammatory reaction from 
radiotherapy usually subsides within 4 weeks after completing radiotherapy, after which PDT 
may be given. 


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6.3.5 Hepatic and Renal Impairment 
Hepatic or Renal impairment will likely prolong the elimination of porfimer sodium leading to 
higher rates of toxicity.  Patients with severe renal impairment or mild to severe hepatic 
impairment should be clearly informed that the period requiring the precautionary measures for 
photosensitivity may be longer than 90 days. 
 
6.3.6 Thromboembolism 
Thromboembolic events can occur following photodynamic therapy with Photofrin®.  Most 
reported events occurred in patients with other risk factors for thromboembolism including 
advanced cancer, following major surgery, prolonged immobilization, or cardiovascular disease. 
 
6.3.7 Pulse Oximetry Use Precautions 
In addition, the use of pulse oximetry (pulse ox) exposes the skin to red light, which may cause 
skin burns if left in one place too long.  Up to 30 days or as long as photosensitivity is 
experienced, after receive Photofrin®, care should be taken to have the photo detector/sensor 
device moved to a new location every few minutes.  Use different fingers and toes if necessary.  
Continuous monitoring can carried out by setting up multiple monitors and rotating on and off 
status of the fixed sensors, or by moving a single sensor to different pulsating arteriolar bed, such 
as the finger, great toe, nose, or earlobe.   
 
 
6.4 
Overall Adverse Reaction Profile 
 
Systemically induced effects of photodynamic therapy (PDT) with Photofrin® consist of 
photosensitivity and mild constipation.  All patients who receive Photofrin® will be 
photosensitive and must observe precautions to avoid sunlight and bright indoor light.  
Photosensitivity reactions occurred in approximately 20% of cancer patients and in 69% of high-
grade dysplasia (HGD) in Barrett’s esophagus (BE) patients treated with Photofrin®.  Typically 
these reactions were mostly mild to moderate erythema but they also included swelling, pruritus, 
burning sensation, feeling hot, or blisters.  In a single study of 24 healthy subjects, some 
evidence of photosensitivity reactions occurred in all subjects.  Other less common skin 
manifestations were also reported in areas where photosensitivity reactions had occurred, such as 
increased hair growth, skin discoloration, skin nodule, skin wrinkling and increased skin 
fragility.  These manifestations may be attributable to a pseudoporphyria state (temporary drug-
induced cutaneous porphyria). 
In the Australian study conducted in 136 adult patients, there were no direct serious 
complications from the PDT itself.  One patient died from acute myocardial infarction and 
another suffered a hemiplegia (total paralysis of the arm, leg, and trunk on the same side of the 


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body) after tumor resection.  Three patients had increasing drowsiness (somnolence) and 
hemiparesis (muscle weakness on only one side of the body) associated with cerebral edema 
(excess accumulation of water in the brain) despite usual doses of steroid.  All three cases 
resolved after the use of steroids and diuretics.   
 
In the US pediatric and adult study, two out 20 patients developed complications.  Immediately 
postoperatively, one patient developed severe truncal ataxia (lack of muscle coordination), 
bilateral facial weakness as well as dysphagia (difficulty swallowing).  The other patient who 
underwent an extensive reoperation followed by laser light PDT, had a right facial nerve palsy 
(paralysis), which improved in 3 months, but did not completely resolve. 
 
 
6.5 
Phlebotomy Risks 
 
Inserting a needle for blood sampling can be associated with some discomfort and bruising and, 
although very rarely, inflammation of the arm veins or possible infection. 
 
Infusion reactions: Infusion reactions including urticaria, bradycardia, hypotension, dizziness, 
and hypertension 
 
 
6.6 
Post-Marketing Experience 
 
The following adverse reactions have been identified during post-approval use of Photofrin® 
with PDT.  Because these reactions are reported voluntarily from a population of uncertain size, 
it is not always possible to reliably estimate their frequency or establish a causal relationship to 
drug exposure.   
 
 
6.7 
Concurrent Anticancer Therapy 
 
Concurrent anticancer therapy not defined within this protocol, including chemotherapy, 
radiation therapy, immunotherapy, or biologic therapy may NOT be administered to patients 
receiving study drug (from Day –30 to Day +30).  If anticancer therapeutics are administered to 
the patient during this time he or she may (1) not be permitted to begin protocol therapy, (2) be 
removed from protocol therapy, (3) be considered inevaluable for toxicity review and/or survival 
analyses.  
 
 
6.8 
Other Investigational Agents 


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Other investigational agents not specified in this protocol may NOT be given while the patient is 
on protocol therapy, or during the first month follow-up for toxicity review. 
 


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7.0 
INVESTIGATIONAL DRUG AND DEVICE INFORMATION 
 
 
7.1 
Photofrin ® (porfimer sodium, 75 mg) for Injection 
 
7.1.1 Description 
Photofrin® (porfimer sodium) for Injection is a photosensitizing agent used in the 
photodynamic therapy (PDT) of tumors and of high-grade dysplasia (HGD) in Barrett’s 
esophagus (BE).  Following reconstitution of the freeze-dried product with 5% Dextrose 
Injection (USP) or 0.9% Sodium Chloride Injection (USP), it is injected intravenously.  This 
is followed 40–50 hours later by illumination of the tumor or HGD in BE with laser light 
(630 nm wavelength).  Photofrin
® is not a single chemical entity; it is a mixture of oligomers 
formed by ether and ester linkages of up to eight porphyrin units.  It is a dark red to reddish 
brown cake or powder.  Each vial of Photofrin
® contains 75 mg of porfimer sodium as a 
sterile freeze-dried cake or powder.  Hydrochloric Acid and/or Sodium Hydroxide may be 
added during manufacture to adjust the pH to within 7.2 – 7.9.  There are no preservatives or 
other additives.  The structural formula below is representative of the components present in 
Photofrin® 
 
7.1.2 Pharmacology 
The cytotoxic and antitumor actions of Photofrin® are light and oxygen dependent.  
Photodynamic therapy with Photofrin® is a two-stage process.  The first stage is the intravenous 
injection of Photofrin®.  Clearance from a variety of tissues occurs over 40-72 hours, but tumors, 
skin, and organs of the reticuloendothelial system (including liver and spleen) retain Photofrin® 
for a longer period.  Illumination with 630 nm wavelength laser light constitutes the second stage 
of therapy.  Tumor selectivity in treatment occurs through a combination of selective retention of 
Photofrin® and selective delivery of light.  Cellular damage caused by Photofrin® PDT is a 
consequence of the propagation of radical reactions.  Radical initiation may occur after 
Photofrin® absorbs light to form a porphyrin excited state.  Spin transfer from Photofrin® to 
molecular oxygen may then generate singlet oxygen.  Subsequent radical reactions can form 
superoxide and hydroxyl radicals.  Tumor death also occurs through ischemic necrosis secondary 


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to vascular occlusion that appears to be partly mediated by thromboxane A2 release.  The laser 
treatment induces a photochemical, not a thermal, effect.  The necrotic reaction and associated 
inflammatory responses may evolve over several days. 
 
7.1.3 Pharmacokinetics 
Following a 2 mg kg-1 dose of porfimer sodium to 4 male cancer patients, the average peak 
plasma concentration was 15 ± 3 mcg/mL, the elimination half-life was 250 ± 285 hours, the 
steady-state volume of distribution was 0.49 ± 0.28 L kg-1, and the total plasma clearance was 
0.051 ± 0.035 mL min-1 kg-1.  The mean plasma concentration at 48 hours was 2.6 ± 0.4 mcg mL-
1.  The influence of impaired hepatic function on Photofrin® disposition has not been evaluated. 
 
Photofrin® was approximately 90% protein bound in human serum, studied in vitro.  The binding 
was independent of concentration over the concentration range of 20–100 mcg mL-1. 
 
The pharmacokinetics of Photofrin® was also studied in 24 healthy subjects (12 men and 12 
women) who received a single dose of 2 mg kg-1 Photofrin® given via the intravenous route.  The 
serum decay was bi-exponential, with a slow distribution phase and a very long elimination 
phase.  The elimination half-life was 415 ± 104 hours (17 ± 4.3 days).  Cmax was determined to be 
40 ± 11.6 mcg/mL and AUCinf was 2400 ± 552 mcg × hourmL-1.  Women had a lower Cmax and a 
higher AUC.  The clinical significance of these differences is unknown.  Tmax was approximately 
1.5 hours in women and 0.17 hours in men.  At the time of intended photoactivation 40-50 hours 
after injection, the pharmacokinetic profiles of Photofrin® in men and women were similar. 
 
7.1.4 Drug Interactions 
There have been no formal interaction studies of Photofrin® and any other drugs.  However, it is 
possible that concomitant use of other photosensitizing agents (e.g., tetracyclines, sulfonamides, 
phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, and 
fluoroquinolones) could increase the risk of photosensitivity reaction. 
 
Photofrin® PDT causes direct intracellular damage by initiating radical chain reactions that 
damage intracellular membranes and mitochondria.  Tissue damage also results from ischemia 
secondary to vasoconstriction, platelet activation and aggregation and clotting.  Research in 
animals and in cell culture has suggested that many drugs could influence the effects of PDT, 
possible examples of which are described below.  There are no human data that support or rebut 
these possibilities. 
 
Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, 
β-carotene, ethanol, formate and mannitol would be expected to decrease PDT activity.  
Preclinical data also suggest that tissue ischemia, allopurinol, calcium channel blockers and some 


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prostaglandin synthesis inhibitors could interfere with Photofrin® PDT.  Drugs that decrease 
clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could decrease 
the efficacy of PDT.  Glucocorticoid hormones given before or concomitant with PDT may 
decrease the efficacy of the treatment. 
 
7.1.5 Carcinogenesis, Mutagenesis, Impairment of Fertility 
No long-term studies have been conducted to evaluate the carcinogenic potential of Photofrin®.  
In vitro, Photofrin® PDT did not cause mutations in the Ames test, nor did it cause chromosome 
aberrations or mutations (HGPRT locus) in Chinese hamster ovary (CHO) cells.  Photofrin® 
caused < 2-fold, but significant, increases in sister chromatid exchange in CHO cells irradiated 
with visible light and a 3-fold increase in Chinese hamster lung fibroblasts irradiated with near 
UV light, Photofrin® PDT caused an increase in thymidine kinase mutants and DNA-protein 
cross-links in mouse L5178Y cells, but not mouse LYR83 cells.  Photofrin® PDT 
 
Pregnancy Category C:  Porfirmer sodium has been shown to have an embryocidal effect in 
rats and rabbits when given in doses 0.64 times the recommended human dose on a [mg m-2] 
basis.  Porfimer sodium given to rat dams during fetal organogenesis intravenously at 0.64 times 
the clinical dose on a [mg m-2] basis for 10 days caused no major malformations or 
developmental changes.  This dose caused maternal and fetal toxicity resulting in increased 
resorptions, decreased litter size, delayed ossification, and reduced fetal weight.  Porfimer 
sodium caused no major malformations when given to rabbits intravenously during 
organogenesis at 0.65 times the clinical dose on a [mg m-2] basis for 13 days.  This dose caused 
maternal toxicity resulting in increased resorptions, decreased litter size, and reduced fetal body 
weight. 
 
Porfirmer sodium given to rats during late pregnancy through lactation intravenously at 4  
[mg m-2 per day] (0.32 times the clinical dose on a [mg m-2] basis) for at least 42 days caused a 
reversible decrease in growth of offspring.  Parturition was unaffected. 
 
There are no adequate and well-controlled studies in pregnant women.  Photofrin® should be 
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
 
Nursing Mothers:  It is not known whether this drug is excreted in human milk.  Because many 
drugs are excreted in human milk and because of the potential for serious adverse reactions in 
nursing infants from Photofrin® women receiving Photofrin® must not breast feed. 
 
Pediatric Use:  Safety and effectiveness in children have not been established. 
 
Use in Elderly Patients:  Approximately 70% of the patients treated with PDT using Photofrin® 


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in clinical trials were over 60 years of age.  There was no apparent difference in effectiveness or 
safety in these patients compared to younger people.  Dose modification based upon age is not 
required. 
7.1.6 Photofrin® Administration 
 
Photofrin® should be administered as a single slow intravenous injection over 3 to 5 minutes at  
2.5 mg kg-1 body weight.  Reconstitute each vial of Photofrin® with 31.8 mL of either 5% 
Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), resulting in a final 
concentration of 2.5 mg mL-1.  Shake well until dissolved.  Do not mix Photofrin® with other 
drugs in the same solution.  Photofrin® reconstituted with 5% Dextrose Injection (USP) or with 
0.9% Sodium Chloride Injection (USP), has a pH in the range of 7 to 8.  Photofrin® has been 
formulated with an overage to deliver the 75 mg labeled quantity.  The reconstituted product 
should be protected from bright light and used immediately.  Reconstituted Photofrin® is an 
opaque solution, in which detection of particulate matter by visual inspection is extremely 
difficult.  Reconstituted Photofrin®, however, like all parenteral drug products, should be 
inspected visually for particulate matter and discoloration prior to administration whenever 
solution and container permit.  Precautions should be taken to prevent extravasation at the 
injection site.  If extravasation occurs, care must be taken to protect the area from light.  There is 
no known benefit from injecting the extravasation site with another substance. 
 
7.1.7 Supplying/Order, Storage, and Handling 
 
Supplied:  Photofrin® (porfimer sodium) for Injection is supplied as a freeze-dried cake or 
powder as follows:  NDC 76128-155-75, 75 mg vial 
 
Supplier:  Pinnacle Biologics, Inc., as subsidiary of Concordia Laboratories Inc. 
 
Agent Ordering:  The study site’s investigational pharmacy will place orders with Pinnacle 
Biologics using their trial specific order form. 
 
Storage:  Photofrin® freeze-dried cake or powder should be stored at Controlled Room 
Temperature 20-25 °C (68-77 °F) [ 
 
Spills and Disposal:  Spills of Photofrin® should be wiped up with a damp cloth.  Skin and eye 
contact should be avoided due to the potential for photosensitivity reactions upon exposure to 
light; use of rubber gloves and eye protection is recommended.  All contaminated materials 
should be disposed of in a polyethylene bag in a manner consistent with local regulations. 
 
Accidental Exposure:  Photofrin® is neither a primary ocular irritant nor a primary dermal 
irritant.  However, because of its potential to induce photosensitivity, Photofrin® might be an eye 


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and/or skin irritant in the presence of bright light.  It is important to avoid contact with the eyes 
and skin during preparation and/or administration.  As with therapeutic over dosage, any 
overexposed person must be protected from bright light. 
7.2 
Photodynamic Therapy (PDT) Lasers 
 
The following PDT Lasers may be used to administer the prescribed light dose of 240 J cm-2, 
with the output laser power at the fiber tip ranging from 1.0 to 4.0 watts.  One or two lasers may 
be used at a time to administer the PDT.  When utilizing two lasers any combination of the laser 
listed or two of the same can be used.  Please notify the Sponsor Investigator and the Industry 
Collaborator, Pinnacle Biologics, Inc. to ensure availability and approval of the PDT Laser for 
each enrolled case. 
 
Angiodynamics DIOMED 630 PDT Laser 
 
Laserscope KTP/532® Surgical Laser System (Series 800) 
 
Laserscope KTP/YAG® Surgical Laser System (Series 800) 
 
 
7.3 
Photodynamic Therapy (PDT) Light Diffusers:  Optical Fibers 
 
Optical fibers serve to diffuse the laser light in the brain tumor cavity.  One optical fiber will be 
needed for each laser.  Optical fibers must be sterilized one time use only.  Currently, the 
protocol is using a spherical light diffuser manufactured by MedLightSA, Model SD200.   


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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
8.1 
Required Clinical and Laboratory and Disease Evaluations  
 
A list of the required clinical and laboratories has been provided in Appendix 1.  This includes a 
table of the study specific and standard of care events and evaluations necessary to answer the 
primary and secondary aims as well as additional evaluations of the patient’s medical records, 
which should be reported in the patients study record for the overall survival analysis and data 
safety monitoring.   
 
 
8.2 
Follow-up 
 
Data from the subjects’ medical records will be collected up to three years following completion 
of the protocol therapy.  Follow-up data are expected to be submitted per the Case Report Forms 
(CRFs) schedule.  This long-term follow-up from Week +5 to Week +156 (3-Year follow-up) 
will be evaluated as clinically indicated, and/or according to their Anti—cancer therapy follow-
up schedule up to Year +3.  During this time, the study coordinator will report data from the 
medical record on study specific CRFs periodically.  Current follow-up data must be reported for 
all required and routine semiannual DSMC reviews, study progress reports, including the FDA 
and IRB Annual Reports. 
 
 
 
 
 


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9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
 
9.1 
Criteria for Removal from Protocol Therapy 
 
1. Refusal of further protocol therapy by patient/legally authorized representative 
2. Physician determines it is in patient’s best interest. 
3. Patient becomes pregnant while on study. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study 
(see below).  Follow-up data will be required unless consent was withdrawn. 
 
 
9.2 
Off Study Criteria 
 
1. Death 
2. Lost to follow-up 
3. Withdrawal of consent for any further data submission 
4. The third anniversary of the date the patient was enrolled on this study 
 
 


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10.0 
STATISTICAL CONSIDERATIONS 
 
 
10.1 
Study Design 
 
This Phase II study includes adults with recurrent high-grade gliomas refractory to first line 
treatment (concurrent radiation and Temodar followed by maintenance Temodar).  Eligible 
patients will consist of individuals with supratentorial recurrent high-grade gliomas that are 
surgically amenable, are not multi-focal and are without leptomeningeal spread.  Eligible patients 
will have injection of Photofrin® at 2.5 mg kg-1, followed by surgical resection of the tumor 24 
hours later.  Craniotomy and tumor resection will be carried out in the standard fashion in order 
to achieve the maximum tumor resection compatible with preservation of neurological function.  
Tissue sample will be evaluated via frozen technique and discussed with the neurosurgeon before 
proceeding with Photofrin® activation.  Patient must have dx of a high-grade glioma before the 
surgery to be a candidate.  Activation of residual Photofrin® in the tumor bed, after resection, 
will be performed using an intra-operative laser with set light dose of 240 J cm-2 and wavelength 
at 630 nm.  Patients will receive standard post-operative care including observation in the post-
anesthesiology recovery unit followed by post-operative computerized tomography (CT) of the 
brain and close monitoring in the neuro-intensive care unit (NICU).  Magnetic resonance 
imaging (MRI) of the brain will be obtained on Day +2 (± 1 day) following the surgery.  An MRI 
will be obtained again at 4 weeks after surgery.  Patient will be closely monitored at Froedtert 
Health-MCW for toxicities associated with Photofrin®. 
 
This is a single arm Phase II study of Photofrin® with set dosing of 2.5 mg kg-1 body weight in 
adult patients with recurrent or refractory high-grade glioma.  The primary objective of this study 
is to evaluate antitumor activity of Photofrin® and laser light activation by evaluating 6 month 
relapse-free as well as overall survival for three years post PDT treatment We will follow 
progression-free survival and overall survival for three years post PDT treatment. 
 
Any individual over the age of 18 with a recurrent/refractory high-grade glioma meeting the 
criteria for the study will be considered a candidate.  Photofrin® will be dosed at 2.5 mg kg-1.  
 
 
10.2 
Sample Size and Study Duration 
 
The sample size is based on a single-arm phase II study designed to detect an increase in the 6-
month relapse-free survival rate from the historical value of 35% (treated as fixed) to 55%.  With 
29 subjects with known 6-month outcome, the study will have 80% power to detect such an 
increase at a one-sided 10% significance level.  This calculation is slightly conservative, because 


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it does not incorporate the increase in the estimated survival rate from censored observations, 
thus the actual power might be slightly higher.  A censoring rate of less than 5% is expected, so 
30 patients will be enrolled in the study.  The following table shows the estimated power of the 
study under various hypothetical values of 6-month relapse-free survival. 
 
6-month RFS 
Power 
45% 
43% 
50% 
64% 
55% 
82% 
60% 
93% 
65% 
98% 
 
 
10.3 
Methods of Analysis 
 
Survival probabilities will be estimated by using the product limit estimate technique.  Overall 
survival and Relapse-free survival will be visualized using Kaplan-Meier plots.  Greenwood’s 
formula will be used to estimate the variance.  The 6-month relapse free survival will be 
compared to the historical control value of 35% via a one-sided z-test at a 10% significance 
level. 
 
 
10.4 
Methods of Analyses for Secondary Objectives 
 
In this single arm phase II trial, the secondary objectives are considered exploratory and will be 
reported descriptively based on appropriate statistical methods and accounting for patients who 
may undergo additional anticancer therapy post documentation of a sustained objective response.  
It is not possible to determine how many patients will provide data that may be used to address 
each of the secondary objectives.  Central review histological diagnoses will be compared with 
diagnoses reported by the treating site.  We will assess the potential impact of any differences on 
primary conclusions of this study.  Considerations will be accounted for when making 
comparisons of survival and disease free survival for recurrent glioma patients.  Refer to 
Appendix 4 
 
 
10.5 
Inclusion of Genders and Minorities 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual to past 
studies of new agents demonstrates the accrual of both genders and all NIH-identified ethnicities 


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to such studies.  The small number of patients entered into this trial will obviate any analysis of 
variation in response rate with gender or ethnicity. 
 


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11.0 
EVALUATION CRITERIA 
 
 
11.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website.  Additionally, toxicities are to be reported on the appropriate case report 
forms.  Refer to sections 12 and 13 for details. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE v4.0 
as referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to version 5.0). 
 
 
11.2 
Methodology to Determine Tumor Measurement 
 
Radiographic response should be determined in comparison to the tumor measurement obtained 
at pretreatment baseline for determination of response, and the smallest tumor measurement at 
either pretreatment baseline or after initiation of therapy should be used for determination of 
progression.  In the event that the radiographic changes are equivocal and it is unclear whether 
the patient is stable or has developed progressive disease, observe the patient closely, for 
example at 4-week intervals.  If subsequent imaging studies demonstrate that progression has 
occurred, the date of progression should be the date of the scan at which this issue was first 
raised.  The determination of radiographic response after treatment with agents, such as 
antiangiogenic therapies, that affect vascular permeability is particularly difficult.  In these 
patients, consideration should be given to performing a second scan at 4 weeks to confirm the 
presence of response or stable disease.  All measurable and nonmeasurable lesions should be 
assessed using the same techniques as at baseline.  Ideally, patients should be imaged on the 
same MRI scanner, or at least with the same magnet strength, for the duration of the study to 
reduce difficulties in interpreting changes. 
 
 
11.3 
Response Criteria  
 
Secondary outcomes will be measured using the response assessment for Neuro-oncology 
(RANO) criteria58 applied to follow-up medical imaging.  Specifically, complete response, 
partial response, stable disease or progressive disease will be determined using volumetric 
measurements of brain tumor enhancement and clinical measures of neurological decline.  
 


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1. Complete response requires all of the following: complete disappearance of all enhancing 
measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; 
stable or improved nonenhancing (T2/FLAIR) lesions; patients must be off 
corticosteroids (or on physiologic replacement doses only); and stable or improved 
clinically.  Note: Patients with nonmeasurable disease only cannot have a complete 
response; the best response possible is stable disease. 
2. Partial response requires all of the following: > 50% decrease compared with baseline in 
the sum of products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; 
stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan; the corticosteroid dose at the time of the 
scan evaluation should be no greater than the dose at time of baseline scan; and stable or 
improved clinically. Note: Patients with nonmeasurable disease only cannot have a partial 
response; the best response possible is stable disease. 
3. Stable disease will require all of the following: does not qualify for complete response, 
partial response, or progression; stable nonenhancing (T2/FLAIR) lesions on same or 
lower dose of corticosteroids compared with baseline scan.  In the event that the 
corticosteroid dose was increased for new symptoms and signs without confirmation of 
disease progression on neuroimaging, and subsequent follow-up imaging shows that this 
increase in corticosteroids was required because of disease progression, the last scan 
considered to show stable disease will be the scan obtained when the corticosteroid dose 
was equivalent to the baseline dose. 
4. Progression will be defined by any of the following: > 25% increase in sum of the 
products of perpendicular diameters of enhancing lesions compared with the smallest 
tumor measurement obtained either at baseline (if no decrease) or best response, on stable 
or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing 
lesion on stable or increasing doses of corticosteroids compared with baseline scan or 
best response after initiation of therapy not caused by comorbid events (e.g., radiation 
therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects); any new lesion; clear clinical deterioration not attributable to 
other causes apart from the tumor (e.g., seizures, medication adverse effects, 
complications of therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose; failure to return for evaluation as a result of death or deteriorating 
condition; or clear progression of nonmeasurable disease. 
 
These criteria are published and currently accepted in the neuro-oncology community58.  The 
imaging interpretation will be completed by a board certified neuro-radiologist, while the 
neurological outcome/status will be assessed by a board certified neurologist/neuro-oncologist. 


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12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
 
12.1 
Purpose 
 
Adverse event (AE) data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who will 
enroll in future studies using similar agents.  Certain adverse events must be reported in an 
expedited manner to allow for timelier monitoring of patient safety and care.  The following 
sections provide information about expedited reporting. 
 
 
12.2 
Expedited Reporting Requirements 
 
 
 
See Next Page… 
 
 


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12.2.1  Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the 
Last Administration of the Investigational Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the Sponsor-
Investigator within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs. 
10 Calendar Days 
Initial Report:  24-Hours 
Full Report:  5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs. 
Not required 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention if they occur within 90 days after the last 
administration of investigational agent/intervention. 
 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
 
 


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12.3 
Expedited Reporting the Sponsor Investigator Examples 
 
12.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Events (SAEs) occurring within 30 days of the last dose, regardless of 
attribution to the investigational agent/intervention requires expedited reporting within 24 hours.  
Any SAE occurring greater than 30 and up to 90 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
 
12.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions (formerly referred to as disabilities), congenital anomalies or 
birth defects, must be reported to the sponsor if it occurs at any time following treatment with an 
agent under an IND/IDE since these are considered serious AEs. 
 
12.3.3 Death 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  Any death 
occurring greater than 30 and up to 90 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
 
Reportable Categories of Death 
 Death attributable to a CTCAE term 
 Death Neonatal: A disorder characterized by cessation of life during the first 28 days of 
life. 
 Sudden Death NOS:  A sudden (defined as instant or within one hour of the onset of 
symptoms) or an unobserved cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5 
 Death NOS :  A cessation of life that cannot be attributed to a CTCAE term associated 
with grade 5 
 Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (includes cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) should be 
submitted. 
 
 


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12.4   Reporting Methods for SAEs 
 
Steps to Determine if an Adverse Event Related to DRUG or the Regimen as a Whole is to 
be Reported in an Expedited Manner 
 
Step 1:  Identify the event type using the NCI Common Toxicity Criteria (CTC), version 
4.0. 
The CTC provides descriptive terminology and a grading scale for each adverse event listed.  A 
copy of the CTC can be downloaded from the CTEP home page (http://ctep.cancer.gov).  
Additionally, if assistance is needed, the NCI has an Index to the CTC that provides help for 
classifying and locating terms.  All appropriate treatment locations should have access to a copy 
of the CTC. 
 
Step 2:  Grade the event using the NCI CTCAE. 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website.  Additionally, toxicities are to be reported on the appropriate case report 
forms.   
 
Step 3:  Determine whether the adverse event is related to the protocol therapy. 
The investigator will assess the causal relationship between the investigational product and the 
adverse event.  The investigator will use his/her clinical expertise and judgment to select the 
attribution category below that best fits the circumstances of the AE. 
 
Attribution Categories:   
Unrelated
Unlikely 
Possible 
Probable
Definite 
 
Unrelated: 
o The adverse event is clearly unrelated to the investigational agent(s). 
o Does not follow a known response pattern to the suspect investigational product 
(if response pattern is previously known) 
o Can be explained by the known characteristics of the patient’s clinical state or 
therapy administered to the patient 
Unlikely: 
a. The adverse event is doubtfully related to the investigational agent(s). 
b. May or may not follow a reasonable temporal sequence from 
administration of the investigational product. 
c. Likely explained by the known characteristics of the patient’s clinical state 


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or other therapy administered to the patient 
Possibly Related: 
a. The adverse event may be related to the investigational agent(s). 
b. Follows a reasonable temporal sequence from administration of the 
investigational product 
c. May also be reasonably explained by the patient’s clinical state or therapy 
administered to the patient. 
d. May follow a known response pattern to the investigational product (if 
response pattern is previously known) 
Probably Related: 
a. The adverse event is likely related to the investigational agent(s). 
b. Follows a reasonable temporal sequence from administration of the 
investigational product 
c. May follow a known response pattern to the investigational product (if 
response pattern is previously known) 
d. Could not be reasonably explained by the known characteristics of the 
patient’s clinical state or other modes of therapy administered to the 
patient, if applicable; 
Definitely Related: 
a. The adverse event is clearly related to the investigational agent(s). 
b. Follows the temporal sequence from administration of the investigational 
product 
c. Follows a known response pattern to the investigational product 
d. Cannot be explained by the known characteristics of the patient’s clinical 
state or other therapy administered to the patient 
e. Is confirmed by improvement of symptoms on stopping or slowing 
administration of the investigational product and re-emergence of 
symptoms on restarting administration of the investigational product, (if 
applicable) 
 
Step 4:  Determine the prior experience of the adverse event.   
Expected events are those that have been previously identified as resulting from administration 
of the agent.  An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in the toxicities listed in the 
drug information section of the protocol. 
 
Step 5:  Report the adverse events as outlined in the protocol. 
 
 


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12.5  Reporting Requirements – Investigator Responsibilities 
 
Clinical investigators in the treating institutions and ultimately the Study Chair have the primary 
responsibility for AE identification, documentation, grading, and assignment of attribution to the 
investigational agent/intervention.  It is the responsibility of the treating physician to supply the 
medical documentation needed to support the expedited AE reports in a timely manner. 
Note: All expedited AEs must also be reported via routine reporting.  Routine reporting is 
accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study database. 
 
 
12.6.1 Additional Protocol Specific Reporting Requirements 
 
12.6.1 Reporting to the Medical College of Wisconsin/Froedtert Hospital IRB 
The Principal Investigator will submit timely reports to the MCW/FH IRB including any 
unanticipated problems, serious adverse device and drug events occurring during the 
investigation, and any deviation from the investigational plan, either unintentional or made to 
protect the life or physical wellbeing of a subject in an emergency.  Any UPIRSO’s, Internal 
Adverse Events, Adverse Device or Drug Effects, or other events meeting the MCW/FH IRB 
prompt reporting criteria will be reported no later than 5 calendar days after the study team 
becomes aware of the problem, event or information.  All other adverse events will be reported at 
time of continuing review in accordance with MCW/FH IRB policy.  Non–serious Adverse 
Events (collected from Day 0 to Day +30/1-Month follow-up) and non-serious/administrative 
protocol deviations will be collected and reported on an annual basis as per MCW/FH IRB 
policy.  SAEs (collected from Day 0 to Day +90) that are unrelated to the study will be reported 
to the IRB on an annual basis via the DSMC Study progress reports.  Refer to section 13.3 for 
details.  SAEs require DSMC expedited review will be reported to the IRB within 5 calendar 
days. 
 
12.6.2 Reporting to Pinnacle Biologics, Inc. 
The industry collaborator, Pinnacle Biologics, Inc. is an international company with obligations 
in several European countries to quickly report all SAEs from all ongoing clinical trials using 
Photofrin®.  We have developed a reporting plan that will facilitate Pinnacle’s reporting 
requirements while safeguarding patient’s confidentiality. 
 
Reporting Serious AEs:   
The investigator will report each SAE, regardless of causality, within 24 hours of awareness by 


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e–mail, or fax to the Pinnacle Biologics, Inc. third party Drug Safety delegate.  This includes 
SAEs occurring as soon as the patient or patient’s legally representative signs the informed 
consent (i.e., pre–treatment SAEs).  The SAE form provided by Pinnacle Biologics, Inc. should 
be completed as thoroughly as possible, given the information available and time constraints. 
A full initial report accompanied by additional relevant information documenting the occurrence 
of the event should be forwarded to the Drug Safety delegate within 4 calendar days (in case of 
death or life–threatening events) or 7 calendar days (for other SAEs) respectively.  Follow up 
report should be forwarded within the next 5 calendar days (in case of death or life–threatening 
events) or as soon as this information is available (for other type of events). 
 
In addition, any spontaneously reported SAE that occurs within 30 days after the last study 
procedure for patient who completed the study protocol or within 90 days after the Photofrin® 
injection for patients who prematurely discontinued study treatment should be recorded and 
reported. 
 
Other Events Requiring Expedited Reporting: 
The following events should be also reported to the Drug Safety delegate within 24 hours of 
awareness: 
• Any pregnancy that occurs to study patients.  Drug exposure during pregnancy should be 
reported on the “Pregnancy Exposure form” provided by Pinnacle Biologics, Inc. 
• Drug or light dose overdose with or without adverse events 
• Inadvertent or accidental exposure to the study drug with or without adverse events 
• All other medication errors (use of expired medication, dosing errors, etc.) with or 
without adverse events 
• Suspected transmission of an infectious agent 
• SAEs that meet the criteria for expedited reporting to the Data Safety Monitoring 
Committee for this clinical trial.  Refer to section 13.3. 
 
Reporting Non–Serious AEs 
Non–serious Adverse Events should be collected by the Investigator, but do not require 
expedited report to Pinnacle Biologics, Inc.  Because this protocol is a FDA IND study, these 
events are to be reported periodically (as per FDA regulations) by Pinnacle Biologics, Inc. and 
listed in the final study report.  Listings will be provided to Pinnacle Biologics, Inc. periodically. 
 
12.6.3 Reporting to the Data Safety Monitoring Committee 
Please refer to section 13.3. 
 
 
12.7  Routine Adverse Event Reporting 


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Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) within 
the study database.  For this study, routine reporting will include all expedited reportable events 
and Grade 3 and higher Adverse Events. 
13.0 
STUDY DATA COLLECTION AND SAFETY MONITORING 
 
 
13.1 
Data Management 
 
This Cancer Center CTO will report clinical trial data using The Online Enterprise Research 
Management Environment (OnCore™), a web based Oracle® database utilizing study specific 
trial management tracking forms.  Key study personnel are trained on the use of OnCoreTM and 
will comply with protocol specific instructions embedded within the OnCoreTM forms.  Patient 
demographics, patient specific study treatment calendars, adverse events, reporting of deaths, 
and other information required for annual reporting will be placed in OnCoreTM and other 
research databases maintained by MCW IT. 
 
 
13.2  Case Report Forms 
 
Initial Plans:  Participant data will be collected using protocol specific case report forms 
developed by the sponsor.  The CRFs will be approved by the study’s Principal Investigator and 
the Biostatistician prior to release for use.  The Study Coordinator or designee will be 
responsible for registering the patient at time of study entry, completing CRFs based on the 
patient specific calendar or roadmap, and updating the patient record until the end of required 
study participation. 
 
Implementation of REDCap Database:  Participant data will be collected using protocol 
specific electronic case report forms (e-CRFs) developed within REDCap based on its library of 
standardized forms.  The e-CRF will be approved by the study’s Principal Investigator and the 
Biostatistician prior to release for use.  The Study Coordinator or designee will be responsible for 
registering the patient into REDCap at time of study entry, completing e-CRFs based on the 
patient specific calendar, and updating the patient record until the end of required study 
participation. 
 
REDCap (Research Electronic Data Capture) is a secure web application for building and 
managing online surveys and databases hosted by the Medical College of Wisconsin (MCW), a 
CTSA consortia partner, who manages and maintains the IT infrastructure and environment in 
which REDCap functions.  This includes the web server and database server, the communication 


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between those two servers, and the communication of the web server with the REDCap end–
user.  MCW hosts REDCap according to typical best practices with the web server and database 
server function two separate servers located securely behind a firewall, as required by 
institutional policy.  Secure access requires a username/password and a Secure Sockets Layer 
Certificate (SSL) is in order to maintain secure communication with the end–user to login to 
REDCap. 
 
This secure, web–based application designed to support data capture for research studies, 
providing:   
1. An intuitive interface for validated data entry 
2. Audit trails for tracking data manipulation and user activity 
3. Automated data export and de–identification procedures for seamless data downloads to 
common statistical packages 
4. Built–in project calendar, a scheduling module, ad hoc reporting tools 
5. Advanced features – branching logic, file uploading, and calculated fields 
 
Monitors, auditors, and other authorized agents of the United States Food and Drug 
Administration, as well as that of any other applicable government agencies, will be granted 
direct access to the study subjects’ original medical records for verification of clinical trial 
procedures and/or data, without violating the confidentiality of the subjects, to the extent 
permitted by the law and regulations.  In any presentations of the results of this study or in 
publications, the subjects’ identity will remain confidential. 
 
 
13.3  Data and Safety Monitoring Plan (DSMP) 
 
The study’s Data and Safety Monitoring Plan will comply with the Medical College of 
Wisconsin Cancer Center's Data & Safety Monitoring Plan (DSMP).  For the purposes of data 
and safety monitoring, this study is classified as moderate risk.  Therefore, the following 
requirements will be fulfilled: 
 
13.3.1 Routine Reporting to the Data Safety Monitoring Committee 
Study Progress Reports:  The PI and Study Statistician will complete and submit a Semi-Annual 
Study Progress Report, every 6 months, to the MCW Cancer Center Data and Safety Monitoring 
Committee (DSMC) with the understanding the MCW DSMC may require more frequent 
reporting.  Contents of the Study Progress Reports will include the information provided in the 
following provided table: 
 
 
Table:  
Content of Routine Study Progress Reports to the DSMC 


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Table:  
Content of Routine Study Progress Reports to the DSMC 
Section 1: Protocol 
Administration 
 Number 
 title 
 PI 
 Dates of IRB approval and activation  
 Listing of agents, dose level, route, 
schedule  
Section 2: Demographics  
 
 Number of patients enrolled 
 M/F 
 ages 
 diagnoses 
 prior treatment 
 performance status 
 disease status 
Section 3: Phase II [per arm]  
 
 Dose 
 number of patients 
 number of courses 
 Adverse event table with frequency and 
severity 
 DLT’s observed 
 SAE’s encountered 
 Efficacy parameters:  response, and 
biomarkers, if applicable 
Section 4: SAE’s 
 All SAE reports  
Section 5: Patient Listing 
 Date enrolled 
 dose level 
 # courses 
 maximum AE severity 
 presence or absence of DLTs observed 
 SAEs 
 overall response 
 overall outcome 
 survival status 
 
13.3.2 Expedited Reporting to the Data Safety Monitoring Committee 
SAEs that will be assessed for trial monitoring/stopping are defined as any of the following 
events with possible attribution to the experimental intervention(s) (the investigational drug, 


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Page 61 of 78 
investigational device, and/or investigational therapy).  This study will utilize version 4.0 of the 
CTCAE of the National Cancer Institute (NCI) for toxicity and performance reporting.  A copy 
of the CTCAE version 4.0 can be downloaded from the CTEP website.  Additionally, toxicities 
are to be reported on the appropriate case report forms.   
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE v4.0 
as referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to version 5.0). 
The DSMC will be notified within 5 calendars days of all serious adverse events occurring 
within 30 days after receipt of protocol therapy, which meets the criteria of one or more of the 
following:  
 
Monitoring of Serious Adverse Events for Stopping Guidelines 
 
1. 
Photosensitivity:   
Skin changes of Grade 4 or higher occurring within 4 weeks of Photofrin® 
injection. 
 
2. 
Ocular Sensitivity:   
Photophobia of Grade 4 or greater occurring within 4 weeks of Photofrin® 
injection. 
 
3. 
Neurotoxicity:   
Attributing a measured decline in neurologic status to either resection or PDT will 
be difficult as many patients have deficits from surgical resection alone.  In 
addition, many patients have significant neurological changes immediately post–
op that improve with time and steroids.  These transient neurological deficits are 
believed to be secondary to acute tissue injury followed by inflammation.  Most 
transient neurological deficits improve within the first month post–op, while fixed 
deficits do not.  Fixed deficits have a greater impact on overall quality of life.  For 
the purposes of this study neurotoxicity will be defined as persistent neurological 
deficits measured at 4 weeks of Grade 4 or greater, or a decline of 2 levels (i.e. 1 
to 3) when compared to pre–operative testing, recorded baseline toxicities.  The 
study team will attempt to localize deficiencies using MRI, clinical exams and 
other testing (i.e. EEG) to the brain outside of the resection, but within the 
penumbra of the photodynamic effect (within 2 cm of the surgical field) to help 
with attribution (surgery versus PDT) when possible. 
 
4. 
Any other hematologic or non–hematologic toxicity Grade 4 or 
higher.   


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Both progression free survival (PFS) and overall survival (OS) will be tracked. 
 
 
13.3.3 Interim Analysis and Stopping Guidelines 
There will be no interim analysis for efficacy (i.e., overall survival endpoint).  Monitoring for the 
safety endpoint of SAE occurrence related to Photofrin®, as determined by the PI, will be 
conducted as described in the next section.  If rates significantly exceed pre-set thresholds, the 
Data and Safety Monitoring Committee (DSMC) will be consulted.  The stopping guidelines 
serve as a trigger for consultation with DSMC for additional review, and are not formal 
“stopping rules” that would mandate automatic closure of study enrollment. 
 
13.3.4 Safety Monitoring and Stopping Guidelines 
To ensure the safety of patients on study, SAEs will be reported by 4 Weeks post PDT as defined 
in section 13.3.1 or section 13.3.2.  The 6-month relapse free survival status will be determined 
based on radiological assessment as defined by section 11 and standard of care medical exam 
carried out at Week +24.  Expected enrollment is 30 patients over the course of 3 years.  The 
stopping guidelines are summarized in the table below. 
 
Table: Stopping Guideline for Dose Limiting Toxicities or 6-month Relapse 
Free Survival 
Number of patients (n)
Stopping boundary (x)
1-6
2
7-12
3
13-18
4
19-30
5
* Stopping guideline is triggered if ≥ x patients out of n experience a SAE with 
attribution to the protocol  
 
 
13.4  Monitoring 
 
The investigator will permit study-related monitoring, audits, and inspections by the applicable 
compliance groups/regulatory bodies.  The investigator will make available all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study 
data, etc.).  The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.) will be available for trial related monitoring, 
audits, or regulatory inspections. 
 
13.4.1 Clinical Site Monitoring 
This protocol will be monitored by an individual or group of individuals from the MCW Cancer 
Center who are not directly or indirectly responsible for the supervision of this trial.  Monitoring 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
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Page 63 of 78 
will occur at a minimum of once per year to ensure all regulatory aspects of this study comply 
with the FDA and any other applicable regulatory boards/bodies. 
 
13.4.2 Supervision of Clinical Trial Reporting 
The Sponsor-Investigator will oversee the submission of all reportable events per the definition 
of reportable in Section 13 to the MCW Cancer Center’s DSMC.  The PI will oversee the 
submission of all reportable events to the FDA, MCW/FH IRB, Industry Collaborators, and other 
required regulatory agencies as outlined in section 12 of the protocol.   
 
 
 
 
13.5  Record Retention 
 
The investigator will retain study records including source data, copies of case report forms, 
consent forms, and all study correspondence in a secured facility for at least 10 years after the 
study file is closed with the IRB and FDA. 
 
In addition, the Cancer Center Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the medical records for 
that patient.  Please contact the CTO before destroying any study related records. 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
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14.0   CONDUCT OF STUDY 
 
 
14.1  Good Clinical Practice 
 
The study will be conducted in accordance with the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol.  Essential clinical documents will be maintained to demonstrate the validity of the 
study and the integrity of the data collected.  Master files should be established at the beginning 
of the study, maintained for the duration of the study and retained according to the appropriate 
regulations. 
 
 
14.2  Ethical Considerations 
 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The IRB will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the patients.  The study will only be conducted at sites where 
IRB approval has been obtained.  The protocol, informed consent, written information given to 
the patients, safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB by the investigator. 
 
 
 


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experimental results of photodynamic therapy in neurosurgery", Proc. SPIE 2371, 5th 
International Photodynamic Association Biennial Meeting, 126 (October 8, 1994). 
 
67. 
Herwig Kostron,Thomas Fiegele, Emra Akatuna. Combination of FOSCAN mediated 
fluorescence guided resection and photodynamic treatment as new therapeutic concept 
for malignant brain tumors. Medical Laser Application Volume 21, Issue 4, 15 November 
2006, Pages 285–290. 
 
68. 
Eljamel M. ALA and Photofrin® Fluorescence-guided resection and repetitive PDT in 
glioblastoma multiforme: a single centre Phase III randomised controlled trial. Lasers 
Med Sci (2008) 23:361–367. 
 
69. 
Matthew Lyons, Isaac Phang, Sam Eljamel. The effects of PDT in primary malignant 
brain tumours could be improved by intraoperative radiotherapy. Photodiagnosis and 
Photodynamic Therapy (2012) 9, 40—45. 
 
70. 
Eljamel S. Photodynamic applications in brain tumors: A comprehensive review of the 
literature. Photodiagnosis and Photodynamic Therapy (2010) 7, 76-85. 
 
71. 
Muller P, Wilson B.  A randomized two arm clinical trial of Photophrin PDT and 
standard therapy in high grade gliomas.  Phase III trial.  In: Proceedings of the 6th 
international PDT symposium.  2006. 
 
72. 
Muller P. Photodynamic Therapy of Brain Tumors—A Work in Progress.  Lasers in 
Surgery and Medicine 38:384–389 (2006) 
 
73. 
Dougherty TJ. Photodynamic Therapy (PDT) of Malignant Tumors. CRC Critical 
Reviews in Oncolology/Hematology. 2(2):83-116, 1984. 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 72 of 78 
STANDARD OF CARE & STUDY 
SPECIFIC EVENTS & 
EVALUATIONS 
PRE–STUDY 
TREATMENT PHASE 
POST-OP FOLLOW–UP 
LONG–TERM FOLLOW–UP 
Day –30 To Day 0 
Day 0:  
Photofrin® 
Day +1:  PDT 
Photoillumination 
Day +2 To Discharge:  
Post–Op Care 
Week 1 To 4 (Week No.): 
Week 5 to 13: 
(Patient SOC Plan) 
Week 24: 
(6 Months Post PDT) 
Week 52 to 156: 
(Patient SOC Plan) 
1 
2 
3 
4 
SCREENING 
Neuro-Oncology Eligibility Review 
X 
X 
 
 
 
 
 
 
 
 
 
ENROLLMENT & REGISTRATION 
Informed Consent 
X2 
 
X 
 
 
 
 
 
 
 
 
HIPAA Authorizations for Follow-Up Reports 
X2 
 
 
 
 
 
 
 
 
 
 
Eligibility Checklist & Registration CRFs 
X2 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
Photofrin® Dose Calculation, Preparation, & 
Duration (Start & Stop Time) 
 
X2 
 
 
 
 
 
 
 
 
 
Tumor Resection 
 
 
X 
 
 
 
 
 
 
 
 
PDT Photoillumination Dose Calculation, 
Preparation, & Duration (Start & Stop Time) 
 
 
X2 
 
 
 
 
 
 
 
 
ACUTE POST–OP CARE 
Dexamethasone Dose 
 
 
X1 
X1 
X1 
X1 
X1 
X1 
 
 
 
Intracranial Pressure Monitoring 
 
 
X1 
X1 
 
 
 
 
 
 
 
LABS  
CBC 
X 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
BUN 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
Creatinine 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
ALT 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
AST 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
Total Bili 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
ALK 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
PT 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
PTT 
X2 
 
 
X1 
X1 
X2 
X1 
X1 
X1 
 
 
Other 1
X1 
 
 
X1 
X1 
X1 
X1 
X1 
X1 
 
 
EVALUATIONS 
H & P  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X1 
 
 
Karnofsky Score 
X 
 
 
X 
X 
X 
X 
X 
X1 
X 
X1 
Neurologic Exam 
X 
 
X 
X 
X 
X 
X 
X 
X1 
X 
X1 
MRI Brain 
X 
 
 
X 
X1 
X1 
X1 
X 
X1 
X 
X1 
MRI Total Spine 
X1 
 
 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Required CTCAE Reporting [Grade(s)] 
 
1–5 
1–5 
1–5 
1–5 
1–5 
1–5 
1–5 
3 – 5 
 
 
All Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X1 
 
 
Anti-Cancer Therapy: Chemo/XRT/Surgery 
 
 
 
 
 
 
 
 
X 
X 
X 
Disease Evaluations 
 
 
 
 
 
 
 
 
X1 
X 
X1 
Survival Status/Cause of Death (if applicable) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  Required Reporting & SOC for the Patient 
 
X1 Recorded IFF Clinically Indicated According to the Patient’s SOC 
 
X2  Required Study Event; Not SOC 
APPENDIX 1:  PHOTODYNAMIC THERAPY (PDT) EVALUATION TABLE 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 73 of 78 
APPENDIX 2:  PATIENT INFORMATION SHEET 
 
What is photodynamic therapy? 
 
Photodynamic therapy (PDT) is an experimental treatment for brain tumors in adults.  PDT has 
been used successfully in adults with high-risk, brain tumors that recurred after treatment with 
chemotherapy or radiation therapy.  PDT uses a medicine called Photofrin® given into a vein that 
accumulates in tumor cells more than normal cells.  The brain tumor is surgically removed and 
then Photofrin® in the remaining tumor cells is activated by light delivered by a laser at the time 
of surgery.  Light-activated Photofrin® then kills the tumor cells. 
 
How is this medicine given, and what are its side effects? 
 
Photofrin® is given intravenously (IV), or into a catheter in a vein, the day before surgery.  
Medicines that are given IV may affect cells in many parts of the body.  As a result, it is 
important for you to know that this medicine will make your skin and eyes very sensitive to 
bright light for at least 30 days and up to 90 days after it is given.  You need to follow special 
precautions to protect yourself from serious side effects from exposure to bright light during this 
time.  Sunburn-like reactions, including redness, itching, a burning sensation, a feeling of 
warmth, and discomfort on exposed skin, can occur.  In severe reactions, blisters and swelling 
develop.  When these reactions are seen, it is called phototoxicity.   
 
On the day you receive Photofrin® , it is important to take the following actions: 
 
• Close your window shades at home before you come to the hospital 
• Wear the following protective items, or bring them to the hospital to wear home:  
o Dark sunglasses (light transmittance of less than 4%) 
o Gloves (canvas or leather, not knit) 
o Wide-brimmed hat (not straw) 
o Long-sleeved shirt (tightly woven fabric that does not allow light to penetrate) 
o Scarf, pants, socks and shoes 
• For individuals who drive, please note that dark sunglasses may impact your ability to 
drive or use machinery.  As a result, be sure you have transportation home from the 
hospital. 
 
Are there any special precautions while on this medication? 
 
For at least the first 30 days after receiving Photofrin®, it is important to take the following 
actions: 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 74 of 78 
• Avoid bright light.  Examples of bright light include the following: 
o Direct sunlight, including direct light from skylights 
o Neon lights 
o Halogen and spotlights 
o Un-shaded light bulbs at close proximity 
o Exam lights used by health care providers, including a dentist or an eye doctor 
o Tanning salon lights 
o Make-up lights 
• Wear protective items, as described above, if you must be exposed to bright light.  Avoid 
bright light and going outdoors during the day, if at all possible. 
• Wear dark sunglasses when outdoors. 
• If you travel to a different geographic area, be sure to retest your skin’s level of 
sensitivity to light in the new location. 
• Watching TV or using a computer is fine. 
• Remember that some individuals may remain sensitive to light for up to 90 days or more.   
 
In addition, there are additional guidelines based on the number of days since Photofrin® 
was given: 
 
• On Days 1-3 after Photofrin® is given: dim the lights indoors and keep the curtains and 
blinds closed. 
• On Days 4-14 after Photofrin® is given: keep the curtains and blinds closed, but you no 
longer need to dim the lights indoors.  Once you have reached the fourth day, exposure to 
normal indoor light is helpful, since it assists the body to inactivate the Photofrin® that 
has reached the skin.  
• On Days 14-30 after Photofrin® is given, keep curtains and blinds closed if the sun is 
coming into the room. 
• On Day 31 after Photofrin® is given, test different areas of skin to determine the level of 
phototoxicity still remaining. 
 
How do I test my skin’s level of sensitivity to light?   
 
The level of sensitivity to light will vary for different areas of the body.  Before exposing any 
area of skin to direct sun or bright indoor light, you should test that area’s sensitivity to light.  
See an example of how to test your skin’s level of sensitivity to light listed below. 
 
Test Instructions: 
• Cut a 2-inch hole in a paper bag and put your hand in the bag. 
• Expose only this area to sunlight for 10 minutes.  Keep the rest of your skin covered. 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 75 of 78 
• The next day, check if your skin shows a reaction.  If you do not get a red area, swelling, 
or blisters, you can then gradually resume normal outdoor activities.  At first, use great 
caution and gradually increase your exposure to light.  Try not to go outside during the 
middle of the day when the sun is brightest. 
• If a phototoxicity reaction occurs with the skin test, you should continue precautions for 
another 2 weeks before retesting this area of skin again.   
• The skin around the eyes is sensitive, so do not use the fact to test the skin’s sensitivity to 
light. 
 
Will sunscreen prevent phototoxicity? 
 
Sunscreen will NOT protect your skin or eyes from phototoxicity.  Sunscreen bought in 
drugstores or in supermarkets is not sufficient because it only protects against ultraviolet light 
and will not protect your skin from visible light. 
 
When should I call a doctor? 
 
• Call the study doctor before taking any new medicines. 
• Call the study doctor if you experience any signs of phototoxicity. 
 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 76 of 78 
APPENDIX 3:  COMMONLY PRESCRIBED PHOTOTOXIC DRUGS 
 
 
This is NOT intended to be a comprehensive list of all Phototoxic medications, but a list of 
medications that are commonly taken by cancer patients.  You should consult your 
physician before taking any new medications, prescribed by a doctor or over the counter, 
in the first three months of the study to determine if these medications could contribute to 
phototoxicity (skin or eye changes). 
 
Antibiotics/Antifungals 
• Quinolones (ciprofloxacin, levofloxacin) 
• Tetracyclines (tetracycline, doxycycline)  
• Sulfonamides (sulfamethoxazole/trimethoprim, clotrimazole)  
• Azoles (voriconazole, itraconazole, terbinafine, griseofulvin) 
• Dapsone 
 
Antihistamines 
• Diphenhydramine 
 
Cancer Chemotherapy Drugs 
• 5-fluorouracil (5-FU, Efudex, Carac, Fluoroplex)  
• Vinblastine (Velban, Velsar)  
• Dacarbazine (DTIC-Dome)  
• Paclitaxel 
 
Cardiac Drugs  
• Amiodarone (Cordarone)  
• Nifedipine (Procardia)  
• Quinidine (Quinaglute, Quinidex)  
• Diltiazem (Cardizem, Dilacor, Tiazac)  
 
Diabetic Drugs  
• Sulfonylureas (chlorpropamide, glyburide, glipizide) 
 
Diuretics 
• Loop diuretics (furosemide, bumetanide) 
• Thiazides (hydrochlorothiazie) 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 77 of 78 
Epidermal Growth Factor Receptors 
• Cetuximab 
• Erlotinib 
• Panitumumab 
• Lapatinib 
 
Malaria Medications 
• Quinine (Quinerva, Quinite, QM-260)  
• Chloroquine (Aralen)  
• Hydroxychloroquine (Plaquenil)  
 
Painkillers 
• Nonsteroidal anti-inflammatory drugs (naproxen, aleve, piroxicam, ibuprofen) 
 
Psychiatric Drugs 
• Phenothiazines (Chlorpromazine)  
• Tricyclic antidepressants (desipramine, imipramine) 
 
Retinoids 
• Isotretinoin (Accutane)  
• Acitretin (Soriatane)  
 
Skin Medications 
• Photodynamic therapy for skin cancer (ALA or 5-aminolevulinic acid (Levulan), Methyl-
5-aminolevulinic acid) 
 
 
 
 


PDT Phase II Trial – Glioma Tumors In Adults 
 
 
 
 
 
Sponsor-Investigator:  Harry T. Whelan, MD 
Confidential 
Page 78 of 78 
APPENDIX 4:  OVERVIEW OF PUBLISHED LITERATURE:  PHOTODYNAMIC THERAPY 
 
Reference 
 [Study Phase] 
 
Type of Brain Tumor 
Photosensitizer 
Light 
Density 
Median Overall (Progression Free) 
Survival [months] 
 
Approach 
N 
GBM 
AA 
Other 
[Dose] 
[J/cm2] 
Group ID 
Primary 
Recurrent 
Stupp59  
[phase 3] 
 
TMZ 
573 
Control 
287 
 
 
 
 
Control 
12.1 (5.0) 
 
TMZ 
286 
TMZ 
14.6 (6.9) 
 
Akimoto60  
[case series] 
 
i/o cavitary spot 
14 
10 
 
4 
Talaporfin sodium 
[40 mg m-3] 
27 
 
26 (23) 
9 (3) 
Muragaki61  
[case series]  
 
i/o cavitary spot 
22 
13 
3 
6 
Talaporfin sodium 
[40 mg m-3] 
27 
27.9 (20) 
24.8 (12) 
 
Stylli62    
[case series]  
 
i/o cavitary Intralipid pool 
136 
78 
58 
 
Hematoporphorin derivative 
(HpD) [5 mg kg-1] 
70-240 
GBM 
14.3 
13.5 
AA 
76.5 
66.6 
Rosenthal63   
[phase 1]  
 
i/o cavitary Intralipid pool 
28 
16 
8 
 
Boronated porphyrin (BOPP) 
[0.25-8 mg kg-1] 
25-100 
GBM 
5 
11 
AA 
 
18 
Schmidtl3  
 [phase 1]  
 
i/o cavitary balloon 
20 
5 
3 
12 
Photofrin® 
[0.75 - 2.0 mg kg-1] 
100 
 
 
 
Stummer64  
[phase 3]  
 
FGR 
243 
Control 
115 
 
Control 
16 
5-ALA 
[20 mg kg-1] 
 
Control 
13.5 (3.6) 
 
FGR 
122 
FGR 
17 
FGR 
15.2 (5.1) 
 
Beck65   [case series] 
 
interstitial 
10 
10 
 
 
5-ALA 
[20 mg kg-1] 
 
 
 
15 
Kostron66  
 [case series]  
 
i/o cavitary superficial 
&interstitial 
58 
50 
 
 
HpD 
[2.5 mg kg-1] 
250 
 
19 
7 
Kostron67 
[phase 3] 
 
i/o cavitary balloon or diffusor 
52 
Control 
26 
 
 
Foscan (mTHPC) 
[0.15 mg kg-1] 
20 
 
3.5 
 
PDT 
26 
 
8.5 
 
Eljamel68 
[phase 3]  
 
FGR post-operative cavitary 
27 
Control 
14 
 
 
5-ALA FGR Photofrin® PDT 
[20 mg kg-1  2 mg kg-1] 
100 
Control 
5.6 (4.8) 
 
 
PDT 
13 
PDT 
12.2 (8.6) 
 
Lyons69   
[phase 2]  
 
FGR post-operative cavitary 
 
repetitive balloon 
 
IORT 
73 
ST 
25 
 
 
 
5-ALA FGR Photofrin® PDT 
[20 mg kg-1  2 mg kg-1] 
100 
ST 
4.6 
 
ST+ PDT          13 
ST+PDT 
9.2 
 
ST+IORT          18 
ST+IORT 
11.2 
 
ST+PDT+IORT  17 
ST+PDT+IORT 
18.2 
 
Muller71, 70  
[phase 3] 
 
unknown 
77 
Control 
34 
 
 
Photofrin® 
[2 mg kg-1] 
120 
Control 
8 
 
PDT 
43 
PDT 
11 
 
Muller72  
[case series] 
 
i/o cavitary balloon & fiber 
96 
49 
24 
26 
Photofrin® 
[2 mg kg-1] 
58 ± 17 
GBM 
7.6 
6.7 
Non-GBM 
15.5 
13.8