Conditions: Locally Advanced Lung Carcinoma Non-Small Cell Lung Carcinoma Small Cell Lung Carcinoma Stage III Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8 Solid Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
This Phase I/Il studies the side effects of endobronchial ultrasound guided interstitial photodynamic therapy work in treating patients with lung cancer that has spread to nearby tissues or lymph nodes. Photodynamic therapy consists of injecting a light sensitive drug called a photosensitizer, such as porfimer sodium, into the vein, waiting for it to accumulate in the tumor, and then activating it with a red laser light. Giving photodynamic therapy with Porfimer sodium may reduce the tumor size in patients with lung cancer.

Detailed description:
PRIMARY OBJECTIVES PHASE 1:

I. To evaluate the safety and potential efficacy of endobronchial ultrasound with transbronchial needle (EBUS-TBN) guided interstitial photodynamic therapy (EBUS-TBN I-PDT) and/or I-PDT and/or photodynamic therapy (PDT) in patients with malignant airway obstructions using porfimer sodium as a photosensitizer.

PRIMARY OBJECTIVE Phase II

* I. To assess the tumor response to treatment.
* II To observe changes in well being

SECONDARY OBJECTIVES:

* I. To evaluate local progression-free survival (PFS).
* II.To compare the treatment planning in DOSIE™ with the plan generated in COMSOL™ - COHORT A ONLY
* III. To measure changes in tumor pO2, optical properties, and irradiance and fluence in relationship to response

EXPLORATORY OBJECTIVES:

I. Examine porfimer sodium retention in the target tumor tissue. II. Examine the relationship between immune biomarkers and response.

OUTLINE:

Patients receive Porfimer sodium intravenously (IV) over 20 minutes delivery of I-PDT. 20 minutes 48 hours +/- 4 hours before receiving I-PDT. I-PDT is then received over 1-2 hours.

After completion of study treatment, patients are followed up at 4, 8, 12, and 24 weeks.

Arms:
arm 1: Treatment (porfimer sodium, EBUS, and photodynamic therapy) Patients receive 2 mg/kg porfimer sodium IV over 3-5 minutes 48 +/- 4 hours prior to the delivery of I-PDT. Patients then undergo EBUS-TBN guided I-PDT over few hours.

Interventions: intervention 1: Porfimer Sodium intervention 2: Ultrasound-Guided Transbronchial Needle-Delivered Interstitial Photodynamic Therapy
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo EBUS-TBN guided I-PDT

Protocol document:
Prot_SAP_000.pdf: 
Document Coversheet 
 
 Study Title: 
Endobronchial Ultrasound Transbronchial Needle guided Interstitial Photodynamic Therapy for 
Palliation of Locally Advanced Lung Cancer and Advanced Cancers Obstructing the Airway -Phase 
I/II Study 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
01/11/2023 
NCT Number: 
NCT03735095 
IRB Number 
I 279415 
 


Roswell Park Protocol No.: I 279415
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TITLE: Endobronchial Ultrasound Transbronchial Needle Guided Interstitial 
Photodynamic Therapy for Palliation of Locally Advanced Lung Cancer and Advanced 
Cancers Obstructing the Airway -Phase I/II Study
Roswell Park Cancer Institute
Study Number:
I 279415
Initial Date:
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IND Holder:
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Principal Investigator:
Nathaniel Ivanick, MD
Roswell Park Cancer Institute
Elm & Carlton Streets
Buffalo, New York 14263
716-845-8675
Nathaniel.Ivanick@RoswellPark.org
Sponsor:
Roswell Park Comprehensive Cancer 
Center
Industry/Other Supporter:
Concordia International Corp., Oakville, 
ON, Canada
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party(ies) mentioned above (Roswell Park Cancer 
Institute Corporation d/b/a Roswell Park Comprehensive Cancer Center). The use of such 
confidential information must be restricted to the recipient for the agreed purpose and must not 
be disclosed, published, or otherwise communicated to any unauthorized persons, for any 
reason, in any form whatsoever without the prior written consent of the party(ies) above.
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Roswell Park Study Contacts
Study personnel outside of CRS who will be housing essential documents or receiving, analyzing 
or storing biological samples.
Name
Institution
Email
Role
Gal 
Shafirstein, 
DSc
Roswell 
Park 
Cancer 
Institute, 
Buffalo, 
NY
Gal.Shafirstein@RoswellPark.org
Principal 
investigator 
scientific.
Treatment 
planning, 
dosimetry 
analysis. 
Emily 
Oakley, 
PhD
Roswell 
Park 
Cancer 
Institute, 
Buffalo, 
NY
Emily.Oakley@RoswellPark.org
Radiological 
images for 
treatment 
planning, 
drug uptake 
Alan 
Hutson, 
PhD 
Roswell 
Park 
Cancer 
Institute, 
Buffalo, 
NY
Alan.Hutson@RoswellPark.org
Statistical 
analysis
Joseph 
Tario
Roswell 
Park 
Cancer 
Institute, 
Buffalo, 
NY
flowlab@RoswellPark.org
Flow 
Cytometry
Craig 
Brackett, 
PhD
Roswell 
Park 
Cancer 
Institute, 
Buffalo, 
NY
Craig.Brackett@RoswellPark.org
Immune 
markers and 
Analysis 
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Multi-site: use participant initials): ____________________________
Medical Record No.: (Multi-site: use participant initials): ___________________________
Title: Endobronchial Ultrasound Transbronchial Needle Guided Interstitial Photodynamic 
Therapy for Palliation of Locally Advanced Lung Cancer and Advanced Cancer Obstructing 
the Airway-Phase I/II Study
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years of age.
2.
Eligibility checklist before registration requires review of case by study 
surgeon or interventional pulmonologists to approve anatomic 
feasibility of an airway intervention.
3.
For patients in Cohort B only. Patients are amenable to receive a 
palliative radiotherapy of 8 Gy x1 48±4 h prior to the I-PDT, as 
determined by the radiation oncologist. 
4.
Patients with an established pathologic diagnosis of small cell and/or 
non-small cell lung cancer or other malignancies causing airway 
obstruction > 25% requiring bronchoscopic intervention. Or inoperable 
malignancies not candidates for curative radiotherapy within the 
airway.  
5.
Have an ECOG Performance Status of ≤ 3. Refer to Appendix A.
6.
Have the following clinical laboratory values:

Platelets ≥ 100,000 cells/mm3 (SI units100 x 109/L)
7.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.
8.
Participant must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board 
approved written informed consent form prior to receiving any study 
related procedure.
Investigator Signature: ___________________________________
Date: ___________
Print Name of Investigator: ____________________________________________________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Participant Name: (Multi-site: use participant initials): ______________________________
Medical Record No.: (Multi-site: use participant initials): ____________________________
Title: Endobronchial Ultrasound Transbronchial Needle Guided Interstitial Photodynamic 
Therapy for Palliation of Locally Advanced Lung Cancer and Advanced Cancer Obstructing 
the Airway - Phase I/II Study
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Participants who have had curative radiotherapy to the target tumor 
within 4 weeks prior to the scheduled I-PDT and/or PDT.
2.
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
3.
Pregnant or nursing female participants.
4.
Co-existing ophthalmic disease likely to require slit-lamp examination 
within the next 14 days following I-PDT and/or PDT treatment.
5.
Known hypersensitivity/allergy to porphyrin.
6.
Patients who are not cleared by the anesthesiologist to undergo an 
advanced bronchoscopy procedure under general anesthesia.
7.
Patients with target tumor invading into the lumen of the esophagus, 
confirmed by esophago-gastro-duodenoscopy (EGD) with endoscopic 
ultrasound. 
8.
Patients diagnosed with porphyria. 
9.
Unwilling or unable to follow protocol requirements.
10. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive I-PDT or PDT.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Print Name of Investigator: ____________________________________________________
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TABLE OF CONTENTS
1
Background.........................................................................................................................24
2
Rationale.............................................................................................................................40
3
Objectives ...........................................................................................................................41
4
Methodology.......................................................................................................................42
5
Participant Selection ...........................................................................................................45
6
Treatment Plan....................................................................................................................47
7
Investigational Product .......................................................................................................55
8
Study Procedures ................................................................................................................57
9
Efficacy evaluations............................................................................................................71
10
Safety Evaluation................................................................................................................73
11
Data and Safety Monitoring................................................................................................77
12
Statistical Methodology......................................................................................................78
13
Ethical and Regulatory Standards.......................................................................................83
14
Study Responsibilities ........................................................................................................84
15
Administrative Rules ..........................................................................................................84
16
Appendices .........................................................................................................................86
17
References.........................................................................................................................110
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1
BACKGROUND
1.1.1
 Lung Cancer with Airway Obstruction
Lung cancer may be cured in its early stages with surgical resection. Unfortunately, the majority 
of patients with lung cancer are presented in later stages where chemotherapy, with or without 
radiation, is the preferred treatment. Advanced disease stage carries poorer prognosis, with low 
survival rates. (1, 2)
Patients with late-stage lung cancer may be presented with tracheal or bronchial airway 
obstruction. These patients are at higher risk for respiratory failure, post-obstructive pneumonia, 
and prolonged hospitalizations. The therapeutic approach for patients with malignant airway 
obstruction is usually complicated and challenging and, includes bronchoscopic intervention, 
radiation therapy, or both, in combination with chemotherapy. Some patients resist chemoradiation 
therapy (CRT) or, are not able to tolerate the CRT because of other medical co-morbidities. In 
these instances, their disease continues to progress with persistent airway obstruction, requiring 
palliation and life-saving interventions with one or more bronchoscopic procedures. 
Bronchoscopic intervention leads to faster improvement but requires an advanced bronchoscopic 
procedure using laser, cryotherapy, tumor debulking, and ablation with or without airway stenting. 
Patients at this terminal stage tend to progress with recurrent airway obstruction, which can lead 
to repetitive palliative bronchoscopic procedures.
Additionally, a variety of malignancies can create malignant central airway obstruction, including 
lung, breast, colon, thyroid, adenoid cystic, various head and neck malignancies, renal cell, and 
others.  Other non-epithelioid malignancies, including melanoma can also cause central airway 
obstruction. Intraluminal PDT has been used to treat any malignancy metastatic to the airway.  
Reddy et al. published a case series treating malignant central airway obstruction due to renal cell 
carcinoma. (3)  Magro et al. published a case series treating a variety of metastatic central airway 
obstruction using PDT with similar promising results (4) when treating carcinomas of the colon, 
breast, kidney, and tongue that were metastatic to the airways.  Other authors have demonstrated 
that PDT, when applied to metastatic tumors of the central airways, was able to significantly 
improve the degree of obstruction and quality of life these patients experienced. (5)
All of the above authors used intraluminal PDT to direct their treatment. Thus, we will use same 
I-PDT treatment approach for all malignancies that compromise the airway in this study. 
1.1.2
Photodynamic Therapy for Bronchogenic and Esophageal Cancer
The U.S. Food and Drug Administration (FDA) approved the use of porfimer sodium mediated 
PDT for the treatment of esophageal cancer, NSCLC, and High-Grade Dysplasia in Barrett’s 
Esophagus.(6, 7) PDT with Photofrin® (porfimer sodium) has been approved for the treatment 
of non-small cell lung cancer (NSCLC) for over 15 years (6, 7). In PDT, systemic administration 
of a light sensitive drug (i.e., photosensitizer, PS) is followed by illumination of the target tumor 
with visible light that leads to the generation of reactive oxygen species, notably singlet oxygen, 
(8) resulting in the destruction of the tumor by a combination of direct cellular and secondary 
vascular effects. (9) In addition to local tumor ablation, PDT has been shown to enhance anti-
tumor immunity in both clinical and pre-clinical settings. (10-12) PDT is also used as a single-
therapy or, in combination with surgery, chemotherapy, or standard radiation therapy. (13-15)  
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Several retrospective studies suggested that Photofrin® mediated PDT with chemotherapy could 
improve the outcomes for patients with advanced esophageal cancer, and for patients with 
unresectable cholangiocarcinoma.(16) Photofrin® mediated PDT + chemotherapy has been 
reported to be better than either PDT alone or chemotherapy alone in the treatment of unresectable 
cholangiocarcinoma and advanced esophageal cancer in a limited number of studies.(16, 17) A 
relatively large retrospective study by Lindenmann et al. (18) suggested that adding Photofrin® 
mediated PDT prior to standard of care (n=118) resulted in better overall survival than adding PDT 
after standard of care (n=130) in patients with inoperable esophageal cancer. (18) That report was 
in agreement with Li et al.’s study ( 2010) (16) which found that Photofrin® mediated PDT before 
chemotherapy (n=33) is associated with significantly better overall response when compared with 
either Photofrin® mediated PDT (n=27) or chemotherapy alone (n=30) in patients with advanced 
esophageal cancer.(16) 
PDT’s primary indication is for obstructive disease and symptom palliation in patients with tumors 
that are not eligible for standard surgery and radiation therapy. Currently, the most commonly used 
photosensitizer in PDT is Photofrin® (Pinnacle Biologics Inc. Bannockburn, IL). After intravenous 
injection, Photofrin® is retained in neoplastic cells and, to a lesser degree, in normal tissue. The 
therapeutic effect is obtained by illuminating the target tumor and margins with visible light with 
630 ± 3 nm wavelength, approximately 48 hours post-administration. (19-21) Photosensitivity is 
the major complication of PDT with Photofrin®. The photosensitivity usually lasts for 4-6 weeks. 
During that time, patients are instructed to use sunglasses to protect the eyes and cover the skin 
with long sleeve shirts and pants, when exposed to direct sunlight or bright indoor light. The 
development of second-generation PSs has minimized photosensitivity, by having fast 
accumulation and clearance.
1.1.3
Photofrin® (Porfimer Sodium)
Photofrin® for injection is supplied as a freeze-dried cake or powder as follows: NDC 76128-155-
75, 75 mg vial.
1.1.4
Clinical Use of Porfimer Sodium
The US Food and Drug Administration (FDA) approved the use of porfimer sodium mediated PDT 
for the treatment of esophageal cancer, NSCLC and high-grade dysplasia in Barrett’s esophagus 
(6, 7). In PDT, systemic administration of porfimer sodium is followed by illumination of the 
target tissue with visible light that leads to the generation of reactive oxygen species, notably 
singlet oxygen (8). Porfimer sodium is being used off label and in clinical studies to treat many 
other cancers (10, 22-24).
Porfimer sodium may last for at least 30 days within the primary tumor.
A detailed description of the specific indications and, discussion of the clinical pharmacology, 
pharmacokinetics, and toxicology of porfimer sodium can be found in the Photofrin® User’s 
Guide.
1.1.5
Endobronchial Ultrasound (EBUS)  
In the past 10 years, convex-probe endobronchial ultrasound (EBUS) became the procedure of 
choice for the mediastinal lung cancer staging. (25) It is widely used for evaluation and diagnosis 
of mediastinal abnormalities such as lymphoma, sarcoidosis, vascular abnormalities, and other 
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tumors. (26-28) Recently, the therapeutic role of EBUS is cautiously emerging with few reports 
of its use in placing fiducial markers for central pulmonary nodules to guide stereotactic body 
radiation (29) and for local injection of chemotherapeutic agents to treat lung cancer. (30-33) 
The EBUS scope consists of a fiber optic component for endobronchial airway visualization and 
a curvilinear ultrasound probe for real-time ultrasound scanning. It also allows the identification 
of vascular structures using the integrated color Doppler. To allow ultrasound scanning of the 
extrabronchial structures, the scope looks at a 35-degree forward oblique angle, with an angle of 
view of 80-degrees. Endobronchial ultrasound with transbronchial needle (EBUS-TBN) is usually 
performed using a dedicated 25-, 22-, 21- or 19-gauge needle with an echogenic tip. These devices 
are equipped with a stylet that is kept in place as the transbronchial puncture is performed and used 
to clean the tip of the needle from any bronchial contamination. The needle can be used to implant 
a laser fiber with cylindrical diffuser in tissue, as discussed below (Section 1.1.7).
1.1.6
EBUS-TBN Guided I-PDT  
1.1.7
EBUS-TBN I-PDT: Phantom Evaluation
The phantom evaluation of optic fiber placement and illumination using EBUS-TBN was 
performed in Roswell Park’s Center for PDT laser laboratory (Dr. Shafirstein, PI) using a solid 
phantom model that mimics the mechanical properties of soft tissue (Ballistic gel, Clear 
Ballistics LLC, Fort Smith, AR). A 21-gauge EBUS needle (NA-201SX-4021; Olympus, Tokyo, 
Japan) was inserted into the phantom model. After cleaning the EBUS needle tip, the stylet was 
withdrawn, and an optical fiber with a cylindrical diffuser was inserted into the needle: the fiber 
is made of flexible polymer that is 3 meters long and 0.5 mm in diameter with a cylindrical 
diffuser end (RD250, Medlight SA, Ecublens, Switzerland). Light is emitted from the cylindrical 
diffuser. The EBUS needle, with the fiber, was pushed to a distal target region in the phantom. 
Thereafter, the needle was withdrawn to expose the cylindrical diffuser end of the optical fiber. 
On the other end, the optical fiber was connected to a diode laser that was used as a light source 
for delivering laser light from the cylindrical diffuser end to the phantom, as shown in Figure 1. 
This experiment revealed the functional placement of using EBUS-TBN in placing the optical 
fiber in a phantom model.
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Figure 1: Image showing the EBUS needle-guided (arrow) placement and illumination of the optic fiber inside the 
phantom model.
1.1.8
In-Vivo EBUS-TBNI for I-PDT 
Five female mice (C3H) bearing SCCVII tumors were used to assess the feasibility of guiding the 
RD250 fiber through a 21-gauge EBUS needle (NA-201SX-4021; Olympus, Tokyo, Japan). The 
curvilinear probe of the ultrasound (Vevo® 2100, VisualSonics, Toronto, Canada) system was 
used for real-time ultrasound guidance. Each mouse was anesthetized, using isoflurane by 
inhalation, and placed on a small solid platform in a decubitus position with the tumor upward. 
The tumor was covered with a water-based gel and the ultrasound probe was placed in contact 
with the tumor (Figure 2).
Using the jabbing technique, the EBUS needle was inserted into the tumor parallel to the linear 
ultrasound probe. The needle stylet was used to clean the tip of the needle under real-time 
ultrasound visualization. The stylet was removed and the optical fiber that was marked for the 
length of the EBUS needle was introduced up to the needle tip. The fiber was then gently pushed 
outside the needle successfully under real time ultrasound guidance  without any manipulation. 
The fiber was notably hyperechoic and, was easily adjusted inside the tumor under real-time 
ultrasound guidance. The fiber’s appropriate functionality inside the tumor was successfully tested 
with illumination. This procedure was performed in the PDT animal laboratory under an IACUC 
approved protocol.
(A)
(B)
Figure 2: (A) An anesthetized mouse imaged with an ultrasound during interstitial photodynamic therapy using the 
EBUS needle. (B) The ultrasound image of the laser fiber (arrow) within the tumor.
1.1.9
Treatment Planning for I-PDT in Locally Advanced Lung Cancer or Metastatic 
Disease to the Airways  
Recent advancements in computer simulations enable near real-time planning and dosimetry 
during I-PDT. (34-39) We have demonstrated that finite element modeling (FEM) can be used to 
plan the number and location of the optical fibers in the tumor, for an effective illumination of the 
target tumor. (34) A detailed description of this modeling approach is provided in Oakley et al. 
2015. (34) Briefly, an image visualization and analysis software package (Simpleware, Exeter, 
UK) is used to segment tumor, adjacent normal tissues, blood vessels, and other important 
anatomical features. The segmented scans are reconstructed to create a 3-D model that is imported 
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into the FEM software (Comsol Inc., Burlington, MA). The FEM is used to calculate the light 
propagation and absorption in the 3-D model. Figure 3 shows the results of a simulation that was 
conducted on a model created from de-identified CT scans of a patient with locally advanced 
NSCLC. The de-identified scans were obtained with approval from the Roswell Park Cancer 
Institute Office of Research Subject Protection. This was a proof-of-concept simulation to assess 
the possibility of delivering sufficient light dose to a tumor that could be amenable for EBUS-TBN 
guided I-PDT. The simulations suggest that by interstitial illuminating of the tumor with seven 
fibers (RD250) with 4 cm cylindrical diffuser end each, we can administer a light dose of 56.5 
J/cm2 to 100% of the tumor. Each fiber delivers the FDA approved laser light intensity of 400 
mW/cm and energy of 200 J/cm. In this large tumor, the overall I-PDT treatment time would be 
about 1 hr, when fiber is illuminated for 500 s each time.
Recent preclinical studies in Dr. Shafirstein’s laboratory suggest that the irradiance has an 
important impact on tumor response, for I-PDT of locally advanced head and neck cancer. (40, 41) 
We believe that this is also true for I-PDT in LALC. However, in EBUS guided I-PDT for LALC, 
we are limited in the number and location of fibers that we can insert into the tumor. In this 
exploratory study we will aim to administer the new light settings to a significant volume of the 
target tumor. We will administer a 630-nm laser light with the objective to deliver a minimal 
irradiance of ≥8.6, ≥10.8 or ≥15.3 mW/cm2 where we reported effective ablation in Oakley et al. 
2020. (41) The treatment time will be adjusted to deliver ≥45 J/cm2 to a significant volume of the 
target tumor. The research team will present a table showing the light delivery options and percent 
of tumor volume that will receive the minimal irradiance and fluence for the physician to review.
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Figure 3: (A) A three-dimensional (3-D) mesh of a geometry that was reconstructed from CT scans of LALC. (B) 
Close up of 3-D mesh of the tumor with seven 4-cm diffuser fibers (C) The 3-D fluence (J/cm²) distribution on the 
tumor surface, for laser light wavelength of 630 nm with an input light intensity of 400 mW/cm per fiber and a 
treatment time of 500 s per fiber that results in 200 J/cm. The total I-PDT treatment time would be 7X500=3500 s or 
about 1 h. Within the entire tumor, the minimum and maximum fluences would be 56.5 J/cm² and 1273 J/cm², 
respectively. (D) Dose volume histogram for the percent of the tumor volume that receives >45 J/cm² as a 
function of treatment time per fiber, when all seven fibers were on.
COMSOLTM is a commercial non-medical software that we use for treatment planning. An 
alternative option is to use DOSIE™ (Simphotek Inc., Newark, NJ) a novel image-based treatment 
planning for PDT and I-PDT. 
The significance of testing DOSIE™ in this study is:  
1. It will help to address a major unmet need in I-PDT that is the ability to do calculations in 
near real-time, so that the treatment planning is quickly performed during pre-treatment 
phase and can be adjusted in the operating room in case some of the original treatment or 
patient-specific parameters are changed. Currently, simulations are done the day before 
treatment and real-time adjustments cannot be made during treatment. This proposal will test 
the ability of DOSIE™ running in near real-time, which is faster than COMSOL™.
2. The currently available commercial simulation software packages, such as COMSOL™, are 
not tuned for simulations specific to I-PDT and have limited features, which significantly 
limits its ability to be adopted for the clinic. DOSIE™ was designed with help from scientists 
and clinicians at Roswell Park, designated for modeling all types of PDT treatments: I-PDT, 
intracavitary PDT, and external beam PDT (EB-PDT).
3. DOSIE™ entirely owned by Simphotek, collaborator in the NCI/NIH award that will support 
the study to compare DOSIE™ to COMSOL™.  DOSIE™ contains no commercial software 
that would limit its ability to be modified/customized on clinicians’ demand and Simphotek 
long term goal is to obtain FDA approval for DOSIE™ as a treatment planning for PDT and 
I-PDT. 
DOSIE™ is the first image-based treatment planning that is dedicated for PDT and I-PDT. The 
following points set DOSIE™ apart from COMSOL™ with respect to provide a novel image-
based treatment planning. 
1. DOSIE™ is a near real-time system that can be used during clinical treatment in case 
the original treatment parameters are changed in the operating room. 
2. DOSIE™ supports generating treatment plans based not only on the standard light 
dose, but also on the promising new types of doses: thresholding the light irradiance, 
PDT-dose, and singlet-oxygen dose. None of the existing commercial packages offers 
this versatility.
3. DOSIE™ supports simulation of light dose and light irradiance in every cubic 
millimeter of target tumor volume. Two solvers are available for simulation: finite-
element method and Monte Carlo method to estimate the distribution of the light 
scattered within the target volume and at the margins.
DOSIE’s Photokinetics module supports multi-thread simulation of spatially resolved time-
dependent PDT dose and singlet oxygen dose (sOxy) dose (42). The modules are tightly integrated: 
the MC’s output fluence rate map is passed to Photokinetics solver to model PDT dose, with 
modeling photosensitizer’s excitation and photobleaching, and singlet oxygen dose (sOxy) dose, 
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with taking into account oxygen intake and reacted species concentration, that in turn can provide 
calculated concentration of PS excited state molecules as an input to the FE solver to estimate 
distribution of the fluorescent light signal, resulted from the induced fluorescence emission during 
PS radiative relaxation at excitation sites. 
Figure 4. DOSIE™ screenshots: different modes of treatment plan visualization (only one diffuser is on). (a) Tissue 
and tumor irradiance on wireframe, (b) Tumor margins only, (c) Clipping the target volume to visualize interior of 
the tumor. 
1.1.10 EBUS Guided I-PDT Preceded by Standard of Care Palliative Radiotherapy
Following the completion of Cohort 0, we have recently reported that Photofrin® mediated 
interstitial photodynamic therapy (I-PDT), delivered via our image-guided light dosimetry 
planning platform, is safe with promising outcomes in the treatment of extrabronchial MCAO 
with 3 out of 10 patients alive at 8.3, 12, and 26.5 months (56). This study included patients with 
stage IIb-IVb of either non-small cell lung cancer, large cell neuroendocrine, melanoma, or 
endometrial cancer that metastasize to the airway causing extrabronchial MCAO. The 
Photofrin® was retained in all these tumors and responses did not seem to be affected by the 
cancer pathology. Our computer modelling suggests that we delivered the maximum safe light 
dose rate (irradiance) and dose (fluence). Careful analysis of the clinical outcomes indicates that 
further improvement in tumor control requires augmenting I-PDT with additional therapy.
We propose to improve the response to I-PDT with palliative radiotherapy (p-XRT).  P-XRT is  
standard of care treatment for patients with refractory lung cancer (57, 58), and several groups 
have reported that it can increase tumor oxygenation and alter tumor vasculature for 1-2 days 
after the last radiation fraction (59-63). Our group and others have reported that increases in 
tumor hemoglobin oxygen saturation and vascular perfusion will increase tumor oxygenation and 
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penetration of the Photrofrin®-exciting 630-nm illumination laser light (64-68). This is 
accompanied by improvement in tumor response to PDT. 
Preliminary preclinical data demonstrate that p-XRT followed by I-PDT provide for 
constructive cooperation between the modalities. In studies investigating this approach, we 
evaluated the preclinical response of two murine models to a regimen of p-XRT followed in 24 h 
by I-PDT (Figure 5). To demonstrate that p-XRT improves tumor response, we used low dose I-
PDT in mice with locally advanced murine tumors (400-600 mm3).  An X-radiation dose of 10 
Gyx2 on consecutive days induced slight tumor growth delay, establishing it as a palliative 
regimen (palliative X-Radiation, p-XRT). As a standalone modality, the low dose I-PDT 
produced minimal to modest tumor control as a function of tumor model, as expected. When p-
XRT is followed by I-PDT, there is significant (p<0.05) improvement in durable complete 
response in both models (Figure 5).  This 
establishes the benefit of preceding I-PDT with p-
XRT.
 C3H mice with SCCVII
C57BL/6 with Lewis Lung carcinoma 
Figure 5. C3H mice with SCCVII: Tumor growth delay and Kaplan Meier plots for eight- to twelve-week-old C3H mice with 
locally advanced (400-600 mm3) subcutaneous squamous cell carcinoma VII (SCCVII). C57BL/6 with Lewis Lung 
carcinoma (LLC): Eight- to twelve-week-old C57BL/6 mice with locally advanced (400-600 mm3) subcutaneous LLC.  Both 
models treated with I-PDT and palliative radiotherapy (p-XRT) (A) mice treated with p-XRT, (B) mice treated with I-PDT, (C) 
mice treated with p-XRT followed by I-PDT. Cure is defined as no palpable tumor at 60 days (i.e., a complete response) as 
described in Shafirstein et al. 2018. (D) Kaplan Meier plot including control growth, p-XRT, I-PDT, and p-XRT followed I-
PDT. The Log-rank (Mantel-Cox) test found that p-XRT followed by I-PDT resulted in significantly (p <0.05) better tumor 
control when compared to p-XRT only and I-PDT only. The p-XRT regimen was 10 Gy x2 consecutive daily fractions. The 
Photofrin® was administered 1-2 h after the second dose of the p-XRT. The I-PDT was administered with 630-nm light 24±2 h 
after the Photofrin® injection. The laser settings were such that the irradiance and fluence were 6.9 mW/cm2 and 62.5 J/cm2 at 
the margins and 195 mW/cm2 and 1754 J/cm2 at the fiber surface.
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In further studies, we considered the mechanisms behind p-XRT sensitization of tumor to I-PDT.   
Cytotoxic effects of low dose, palliative radiation manifest as temporary control of tumor growth 
and/or partial reduction of tumor burden. This can be accompanied by vascular effects that 
include transient, acute increases in vascular volume and permeability, as well as temporary 
increases in tumor oxygenation. We used photoacoustic imaging to assess the effect of p-XRT on 
tumor hemoglobin and blood oxygenation (Figure 6). At 24 h after p-XRT there was a slight 
increase in hemoglobin compared to the control (no p-XRT in Figure 6 B).  In mice treated with 
p-XRT the tumor blood oxygenation saturation was significantly (p<0.05) higher in comparison 
to the control (Figure 6 C). Relative high blood oxygenation is expected to improve the response 
to PDT due to high oxygen supply and decrease absorption at 630-nm light which will result in 
better light penetration that will allow for treatment of larger tumors (67, 68).  Together, these 
data provide initial evidence that the addition of p-XRT prior to I-PDT can greatly improve I-
PDT outcomes.
In assessing the feasibility of using p-XRT followed by I-PDT to treat very large tumors, we 
recently employed this treatment in a compassionate care exemption setting with Roswell Park 
IRB approval (CE- 22-14). This patient had unusually large extrabronchial MCAO induced by 
Relative Change of
Oxygen Saturation
Relative Change of HbT
no p-XRT
p-XRT
-1.0
-0.5
0.0
0.5
1.0
1.5
no p-XRT
p-XRT
-0.6
-0.4
-0.2
0.0
0.2
0.4
A
B
ns
*
C
Figure 6. Photoacoustic imaging suggests that the p-XRT did not change total hemoglobin and oxygenated 
blood with time. While no treatment resulted in reduction of blood oxygenation when compared to baseline. 
(A) Representative ultrasound and photoacoustic image of LLC tumor. (B) Relative change in hemoglobin 
(HbT) and (C) relative change in percent oxygen saturation of LLC tumors in control (no p-XRT) mice and 
mice treated with p-XRT (10 Gyx2 over two days). Relative change is defined as the difference of 
photoacoustic HbT or percent oxygen saturation signal before and after p-XRT divided by the baseline 
(before p-XRT). Untreated mice had imaging performed at the same treatment volume and same time 
interval, 48 hours apart (n=13 mice per group). C57BL/6 mice with 200-400 mm3 LLC subcutaneous tumors 
(n=13 per group). 
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metastatic renal cell carcinoma of 9.5 cm (Figure 7). In the treatment of this patient, we used p-
XRT (at 8 Gy x1) that 48 h later was followed by our image-guided I-PDT. This single-patient 
treatment was safe and provided benefit in improved breathing and functionality (as seen in the 
CT scan Figure 7B) at 40 days post I-PDT. These results demonstrate the feasibility of using p-
XRT and I-PDT, and suggest that it can provide benefits.
Palliative radiotherapy in patients.  In consultation with the treating radiation oncologist (Dr. 
Malik) who treated the patient on CE 22-14 we propose to treat patients with a standard of care 
single dose of 8 Gy x1 that is expected to be safe, with effective palliation and no significant tumor 
response. This p-XRT regimen was also reported to be safe and induce similar responses when 
compared to other p-XRT regimens for palliation in patients with NSCLC (57, 69).
1.1.11 Correlative Studies
Many NSCLC are infiltrated with immunosuppressive immune cells and these tumor cells are 
known to secrete immunosuppressive cytokines (70, 71) and express immunoregulatory, 
checkpoint molecules that impair anti-tumor immunity. The two best characterized immune 
checkpoints are cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell 
death protein 1 (PD1). (72) CTLA4, through interaction with its receptor, CD28, regulates the 
amplitude of the early stages of T cell activation and enhances Treg cell immunosuppressive 
activity. (73, 74) The primary role of PD1 is to limit T cell activity in the periphery. (75, 76) PD1 
is highly expressed on Treg cells and is associated with increased Treg cell proliferation. PD1 
mediates its effects on T cells upon interaction with its ligands PDL1 (B7-H1) and PDL2 (B7-
DC). PDL1 is expressed by numerous cancer cells (77) and by myeloid cells within the tumor 
microenvironment (78). Numerous clinical trials have been performed using antibodies that inhibit 
immune checkpoints. Blockade of CTLA4 has shown promise in melanoma, but is associated with 
significant immune related toxicities. (72) Blockade of PD1/PDL1 axis has proven to be effective 
in clinical trials of NSCLC with an overall response rate of 20%; PD1/PDL1 blockade also resulted 
in fewer immune toxicity than blockade of CTLA4. (70, 79-82) While extremely encouraging and 
(A)
(B)
9.5 cm
Figure 7.  Treatment outcomes for a patient with locally advanced extrabronchial MCAO induced by metastatic 
renal cell carcinoma treated with 8 Gy x1 followed by our image-guided I-PDT 48 h after the p-XRT.  (A) CT 
scan 13 days prior to treatment showing a 9.5 cm extrabronchial tumor blocking the airway. (B) CT scan 40 days 
after the I-PDT showing open left mainstem airway (marked with a circle) resulting in significant improvement in 
breathing.  
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promising, 80% of patients did not respond to checkpoint blockade, suggesting that additional 
optimization, patient selection and development of combination therapies are needed.
Several recent studies have indicated that treatment of human tumors with photodynamic therapy 
(PDT) can stimulate the host anti-tumor immune response (10, 11, 83) and potentially overcome 
tumor induced immunosuppression allowing for enhanced survival and opening a window for the 
use of immunotherapy. The purpose of these correlative studies is to assess whether treatment with 
biophysical modalities, such as PDT, affects the immune contexture of NSCLC patients. These 
patients tend to have an immunosuppressed immune contexture, which is associated with lower 
overall lymphocytes counts in the periphery, leading to higher neutrophil to lymphocyte ratios 
(NLR) that can be prognostic for treatment outcome (84), elevated levels of circulating regulatory 
T cells, myeloid derived suppressor cells (MDSC), PD1 expressing T cells, and PD-L1 expressing 
MDSCs. (71, 84, 85)
To assess the effect of I-PDT and/or PDT on the immune contexture of study patients we will use 
flow cytometry to examine changes in circulating levels of neutrophils, total lymphocytes 
(CD45+), MDSCs (CD45+, CD11b+, CD33+, HLADRlo, CD14+ or CD15+ and PD-L1+),  cytotoxic 
T lymphocytes (CD45+, CD3+, CD8+, Granzyme B+, Perforin+).  Tumor tissue will be collected 
and used as antigenic material for analysis of tumor specific T cell function (ELISPOT) and 
examined by flow cytometry for changes in PD-L1+ MDSCs and cytotoxic T lymphocytes 
similarly as above in the circulation.
We will use de-identified CT scans from each patient to fabricate 3-D phantoms with 3-D printing 
technology of the airway and tumor. This model will be used to make a mold where we will 
fabricate a phantom with optical properties that mimic the calculated optical properties of the 
tumor. These phantoms will be used to test the accuracy of a new algorithm to compute optical 
properties, and if found accurate it will be considered in future clinical studies.  
1.1.12  Optical and Oxygenation Measurements (optional) 
It has been reported that oxygenated blood has lower absorption coefficient in comparison to  
deoxygenated blood (68). Our group and others have reported that increases in tumor hemoglobin 
oxygen saturation and vascular perfusion will increase tumor oxygenation and penetration of the 
Photrofrin®-exciting 630-nm illumination laser light (64-68). An increase in light penetration and 
tumor oxygenation are expected to be accompanied by improvement in tumor response to I-PDT. 
Therefore, prior to and immediately after delivering the therapeutic 630-nm laser light, we will 
measure tumor tissue partial oxygen pressure (pO2), and we will perform in-vivo spectral 
interstitial transmittance measurements that will provide data that can be used to assess optical 
properties. 
Tumor pO2 will be measured with a validated commercial system (OxyLiteTM Pro, 
Oxford Optronix North America, London, ON, Canada; Oxford Optronix Ltd, Abingdon, UK) 
(86, 87) with a sterile pO2 sensor  ( pO2 'Large Area' sensor, sterile, 5 m length; 1 mm2 
sampling area, Oxford Optronix North America, London, ON, Canada; Oxford Optronix Ltd, 
Abingdon, UK). The sterile pO2 sensor will be placed into a sterile catheter (Bronchial Tube 
sterile, Best Medical International, Inc. Springfield, VA) to achieve rigidity. The end of the 
bronchial tube will be open (prior to treatment) to expose the end of the pO2 sensor that can be 
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inserted into the target tumor for 2-3 min to measure the tumor pO2. The sensor and the catheter 
will then be removed. The sensor and the catheter will be of single use. 
The change in optical properties will be reflected in changes in light irradiance that we have 
shown to affect tumor response and we can measure with a light dosimetry system (40, 41). We 
will measure the transmission of the laser light (for 10-30 s) with an isotropic dosimetry fiber 
(IP, Medlight S.A. Ecublens, Switzerland) that will be connected to our customized light 
dosimetry to measure the transmitted laser light irradiance and fluence.  This system is being 
used in several other Roswell Park IRB approved studies (I 67918, I 62118 and I 767720). The 
isotropic dosimetry fiber is a 3 m long and 1 mm in diameter optical fiber with 0.85 mm in 
diameter distal tip. This fiber will be attached to the outer surface of endoscope so that the 
detection end is at the end of the endoscope. The isotropic dosimetry fiber must be calibrated 
prior to each use. Consequently, the fiber will be submitted to high-level disinfection before and 
after use, following the clinical procedure used to disinfect the endoscope. Then the isotropic 
dosimetry fiber can then be reused in multiple patients.
In addition, we will use the standard endoscope camera to measure the light transmission. To that 
end, we will use a video capture device (USB 3.0 HD Video Capture Device, StarTech, Groveport, 
Ohio) to connect a video output port on the endoscope to a USB port on a password secured 
computer. The streaming software Stream Catcher Pro (StreamCatcherPro, StarTech, Groveport, 
Ohio) will be used in unison with the Startech system to allow for the recording of the endoscope 
video feed. Live feed from the endoscope camera is displayed on the software interface. This 
interface allows the user to name their recording, select the file format the video will be saved as, 
and then start and stop recording. All videos will be taken during treatment. Recordings save 
automatically with the given name and file type immediately upon stopping a recording. This 
process does not interfere with the routine EBUS procedure. It has been tested in Dr. Shafirstein’s 
laboratory using a research clinical system (an Olympus endoscope) that is same as the system 
being used in the clinic.  The recoded data will be saved and analyzed on a password secured 
computer in Dr. Shafirstein’s laboratory.
2
RATIONALE
Chemotherapy remains the mainstay of treating inoperable malignant airway obstruction. Despite 
chemotherapy with one or more regimens, most patients will suffer recurrent disease and may 
present with airway obstruction. Some patients may develop respiratory symptoms (e.g., dyspnea, 
hemoptysis, post-obstructive pneumonia, respiratory failure) secondary to tracheal or bronchial 
obstruction. Palliation of their symptoms is usually accomplished by tumor irradiation or 
bronchoscopic intervention. For some patients, palliative radiation results in clinical improvement 
after partial or complete resolution of the airway obstruction. However, other patients may have 
no response to radiation, which results in disease progression and worsening of respiratory 
symptoms.
Bronchoscopic intervention leads to faster improvement but requires an advanced bronchoscopic 
procedure using laser, cryotherapy, tumor debulking, and ablation with or without airway stenting. 
Patients at this terminal stage tend to progress with recurrent airway obstruction, which can lead 
to repetitive palliative bronchoscopic procedures. There is an urgent need to offer these frail 
patients a treatment with minimal toxicity and morbidity, and that can reduce tumor-induced 
symptoms with a chance to improve their quality of life and perhaps their survival.
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Multiple studies have shown that PDT can lead to tumor regression in lung cancer and other 
malignancies when the tumors are less than 1 cm in thickness. However, I-PDT is required to treat 
large tumors. In recent review papers, we highlighted future directions using I-PDT with treatment 
planning as a possible modality to treat patients with locally advanced cancer including intrinsic 
and extrinsic cancer that compromise the airway and are larger than 1 cm (22, 23). In these tumors, 
EBUS can be used to guide the insertions of the TBN into the tumor and the RD250 laser fiber can 
be inserted through that needle for intra-tumor illumination (Figure 1 and Figure 2). Recently, Dr. 
Shafirstein (Co-Investigator) and his research team published the concept of using EBUS-TBN to 
guide I-PDT in the treatment of locally advanced lung cancer. (90) In addition, I-PDT and/or PDT 
can be used to treat endobronchial tumors. (22)
Our overall hypothesis is that EBUS-TBN guided I-PDT and/or I-PDT and preceded by p-XRT 
are safe and have the potential to treat the bulk of locally advanced lung cancer or other 
malignancies in the central airway, which may lead to tumor regression or slower progression and 
therefore a longer palliation period.
3
OBJECTIVES
3.1.1
Primary Phase I Objective (Cohort 0, data collection completed)

For patients with locally advanced lung cancer (LALC) and malignancies causing 
airway obstructions: To evaluate the safety and potential efficacy of EBUS-TBN 
guided I-PDT and/or I-PDT and/or PDT, using porfimer sodium as a photosensitizer.  
3.1.2
Primary Phase II Objectives (Cohort A  and Cohort B)

To assess the tumor response to treatment.

To observe changes in well-being. 
3.1.3
Secondary Objectives (Cohort A and Cohort B)

To evaluate PFS.

To compare the treatment planning in DOSIETM with the plan generated in COMSOL™ 
in Cohort A only. 

To measure changes in tumor pO2, optical properties, and irradiance and fluence in 
relationship to response. 

3.1.4
Exploratory Objectives (Cohort A and Cohort B)

Examine porfimer sodium retention in the target tumor tissue.

Examine the relationship between immune biomarkers and response.
4
METHODOLOGY
4.1
Study Design
This is a multi-center, multi-arm, Phase I (Cohort 0; data collection complete) to monitor the safety 
and Phase II study (Cohort A and Cohort B described below) to monitor the efficacy of EBUS-
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TBN guided I-PDT and/or I-PDT and/or PDT in patients with malignant airway obstructions that 
are refractory to curative chemoradiation or, who are not candidates for curative chemoradiation. 
Participants will be treated on an outpatient or inpatient basis, and the treating physician will make 
this decision on a case-by-case basis. 
Cohort 0 is closed to accrual and fulfilled the Phase 1 safety monitoring requirements. Cohort 0 
provided the safety monitoring component for Cohort A of this Phase II study. Cohort 0 
consisted of patients with the diagnosis of lung cancer that received porfimer sodium with EBUS 
I-PDT and participated in all of the study procedures except the Quality of Life Questionnaires 
and Six Minute Walk Test.  
Cohort A (n=18, Phase II) consists of patients with a diagnosis of lung cancer or other 
malignancies causing airway obstruction or inoperable malignancies not candidates for curative 
radiotherapy within the airway; and that receive EBUS I-PDT and all of the study procedures.  
Subjects treated in Cohort 0 are considered the Phase I part of Cohort A. 
Cohort B (n=39) will consist of patients with the diagnosis of lung cancer or other malignancies 
causing airway obstruction, or inoperable malignancies not candidates for curative radiotherapy 
within the airway. Subjects in Cohort B will receive the EBUS-guided I-PDT 48±4 h after 
standard of care palliative radiotherapy of 8 Gy x1. 
NOTE: Given the nature of this advanced airway procedure, only the physician performing the 
procedure will be the consenter for the procedure as well as for the study.
All participants will undergo the standard of care interventional bronchoscopy procedure with an 
attempt to treat and resolve the airway obstruction using conventional methods such as mechanical 
debulking, tumor ablation, and/or airway stenting. Airway stenting will be performed before or 
after I-PDT and/or PDT, as necessary. Curvilinear EBUS with Color Doppler will be used to guide 
the intra-tumor fiber insertion.
In each procedure, the estimated percentage of obstruction will be documented before and after 
endobronchial debulking and ablation. Tumor debulking and ablation will be performed before 
EBUS-TBN with I-PDT and/or I-PDT and/or PDT. The airway obstruction severity is usually 
estimated based on the size of scope that can be passed through an obstructed airway and based on 
the size of the balloon used to dilate the obstructed airway.
Airway obstruction severity will be classified as(91): mild (<50%), moderate (50-70%), and severe 
(>70%).
The baseline obstruction to be used in the study will be the airway obstruction that was established 
before the I-PDT and/or PDT. 
It is considered standard of care, and a commonly used approach, to use the Endobronchial 
Ultrasound (EBUS) in combination with therapeutic bronchoscopy. It is useful for diagnostics, as 
well as a tool to guide therapeutic bronchoscopy. EBUS helps demarcate the anatomy of the 
bronchial and peri-bronchial structures such as vascular and cardiac organs and thus, making the 
therapeutic procedure safer. (92)
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For Cohort B participants only, standard of care palliative radiotherapy of 8 Gy x1 will be 
administered to the target tumor at day -2 just before systemic administration of 2 mg/kg porfimer 
sodium. This will be coordinated with the radiation oncologist.
Standard of care blood work and a repeat bronchoscopy and endobronchial ultrasound are 
completed within four weeks (± 2 week) after the airway intervention, depending on the severity 
of the disease and the clinical condition of the patient. A chest CT scan will be performed prior to 
the repeat bronchoscopy to evaluate the airway obstruction and the disease progression.
 
4.1.1
Primary Phase I Endpoint (Cohort 0, data collection completed)

For patients with LALC or other malignancies in the central airway that may extend and 
involve the esophagus: The primary outcome is the safety of the I-PDT using EBUS-TBN 
and/or I-PDT and/or PDT, as measured by toxicity and adverse events (AEs). The AEs will 
be evaluated and graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0.
4.1.2
Primary Phase II Endpoints (Cohort A and Cohort B)

Objective tumor response (CR, PR, PD, and SD)

The FACT-L Total Score related subscale

6-minute walk measures.
4.1.3
Secondary Endpoints (Cohort A and Cohort B)

The number of bronchoscopies

Evaluate progression free survival (PFS)

Compare the treatment planning in DOSIETM with the plan generated in COMSOL™ 
in Cohort A only. 

To measure changes in tumor pO2, optical properties, and irradiance and fluence in 
relationship to response. 
All participants will sign an informed consent prior to study related tests and interventions. All 
participants will meet the inclusion and exclusion criteria summarized in Section 5.1 and 
Section 5.2.
4.1.4
Target Accrual and Study Duration
Eight patients in the Phase I (Cohort 0), and 18 patients will be enrolled in the Phase II Cohort A 
(8 already enrolled under Phase 1 portion of Cohort A from previous protocol version) and 39 in 
Cohort B (65 patients total). It is expected to have up to 32 patients enrolled from accompanying 
external sites and the remainder enrolled from Roswell Park. Accrual is expected to take up to 10 
years.
Patients will be drawn from the interventional pulmonology practice and from referrals from 
medical oncologists. All patients will come off study at 24 weeks.
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Enrolled patients who do not receive the I-PDT and/or PDT for any reason (such as patient 
withdrawal, safety or inability to deliver the I-PDT) will be replaced.
4.1.5
Multi-Site Research
All sites have the most current version of the protocol, consent document, and HIPAA 
authorization.
All required approvals (initial, continuing review and modifications) have been obtained at each 
site (including approval by the site’s IRB of record).
All modifications have been communicated to sites and approved (including approval by the site’
s IRB of record) before the modification is implemented.
All engaged participating sites will safeguard data, including secure transmission of data, as 
required by local information security policies.
All local site investigators will conduct the study in accordance with applicable federal regulations 
and local laws.
All non-compliance with the study protocol or applicable requirements will be reported in 
accordance with local policy.
Refer to Appendix C: Instructions for Multi-Site Studies.
5
PARTICIPANT SELECTION
5.1
Inclusion Criteria
To be included in this study, participants must meet the following criteria:
1. Age ≥ 18 years of age.
2. Eligibility checklist before registration requires review of case by study surgeon or 
interventional pulmonologists to approve anatomic feasibility of an airway intervention.
3. For patients in Cohort B only. Patients are amenable to receive a palliative radiotherapy of 
8 Gy x1 48±4 h prior to the I-PDT, as determined by the radiation oncologist.
4. Patients with an established pathologic diagnosis of small cell and/or non-small cell lung 
cancer or other malignancies causing airway obstruction > 25% requiring bronchoscopic 
intervention. Or inoperable malignancies not candidates for curative radiotherapy within 
the airway.  
5. Have an ECOG Performance Status of ≤ 3. Refer to Appendix A.
6. Have the following clinical laboratory values:
-Platelets ≥ 100,000 cells/mm3 (SI units100 x 109/L)
7. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
8. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure.
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5.2
Exclusion Criteria
Participants will be excluded from this study for the following:
1. Participants who have had curative radiotherapy to the target tumor within 4 weeks prior 
to the scheduled I-PDT and/or PDT.
2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
3. Pregnant or nursing female participants.
4. Co-existing ophthalmic disease likely to require slit-lamp examination within 14 days 
following I-PDT and/or PDT treatment.
5. Known hypersensitivity/allergy to porphyrin.
6. Patients who are not cleared by the anesthesiologist to undergo an advanced bronchoscopy 
procedure under general anesthesia.
7. Patients with target tumor invading into the lumen of the esophagus, confirmed by 
esophago-gastro-duodenoscopy (EGD) with endoscopic ultrasound.
8. Patients diagnosed with porphyria.
9. Unwilling or unable to follow protocol requirements.
10. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive I-PDT or PDT.
5.2.1
Special Populations
The following special populations are excluded from this study:

Cognitively impaired adults/adults with impaired decision-making capacity

Individuals who are not yet adults (infants, children, teenagers)

Prisoners

Pregnant women
5.2.2
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
6
TREATMENT PLAN
Dosing, Administration and Intervention
The following table summarizes the treatment plan for each study cohort.
Cohort
Participant 
disease 
Treatment
Additional therapy 
or intervention
Cohort A
Cancer causing 
airway narrowing.
Participants will be treated with PDT or I-
PDT using treatment planning developed 
by Dr. Shafirstein and the treatment 
None. 
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Or Cancer is not a 
candidate for 
surgery or curative 
radiation therapy. 
planning 
developed 
by 
a 
company 
(Simphotek Inc.).
Cohort B
Cancer causing 
airway narrowing.
Or Cancer is not a 
candidate for 
surgery or curative 
radiation therapy
Participants will be treated with PDT or I-
PDT using treatment planning developed 
by Dr. Shafirstein.
Participants will 
receive one 
treatment of 
palliative 
radiotherapy two 
days before the 
PDT or I-PDT. 
6.1.1
Porfimer Sodium Administration
The intended drug dose of porfimer sodium is 2 mg/kg body weight, administered as a single IV 
dose 48 ± 4 hours prior to the delivery of the therapeutic light (630 ± 3 nm), as clinically approved. 
Drug administration will take place in the Infusion center or the Clinical Sciences Center or in a 
room that has covered windows to protect the subjects from light exposure that can induce 
phototoxicity (i.e., direct sun light or visible artificial light that is more than 60 W). 
A dose of 2 mg/kg of porfimer sodium will be administered by slow intravenous injection into a 
vein (3-5 minutes). 
6.1.2
EBUS and Light Delivery for I-PDT
Treatment will be administered in the Endoscopy suite at Roswell Park Cancer Institute.
All patients will undergo bronchoscopy under general anesthesia, which is the standard of care 
procedure for advanced airway management. The patients will be ventilated using laryngeal mask 
airway (LMA) or endotracheal tube (ETT). The flexible bronchoscope will be used first for airway 
inspection for obstruction evaluation and, images of the airway obstruction will be taken and 
saved. Depending on the nature and characteristic of airway obstruction, rigid bronchoscopy may 
be used during the procedure. When indicated, the airway obstruction will be managed using argon 
plasma coagulation (APC), laser, electrocautery or mechanical debulking. In cases where the 
airway obstruction is solely resulting from extrinsically compressing tumor, the airway will be 
dilated using a controlled radial expansion (CRE) balloon. After establishing airway patency, the 
EBUS scope will be used to identify extrabronchial tumor (tumor that cannot be visualized in the 
airway) around the site of airway obstruction. Color-Doppler will be used to demarcate the tumor 
vasculature.
The pre-treatment plan will follow these steps:

Obtain high-resolution chest CT scan within 2 weeks ± 1-week prior to planned treatment 
with EBUS guided I-PDT.
o
A CT scan with 0.625-1.25 mm slice thickness and slice interval of 0.5-1 mm. The 
CT will be conducted with or without contrast due to known allergy. 
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o
The CT scan will be deidentified to remove all PHI and will only be associated with 
subject study ID.
o
The treating physician will use the deidentified CT scan to mark the target tumor and 
define the sensitive structure, 
o
The marked scan will be provided to Dr. Shafirstein laboratory for treatment 
planning.
o
The team in Dr. Shafirstein’s laboratory will use computer software (Simpleware) to 
generate a 3-D reconstruction of the tumor, airway, blood vessels, and all clinically 
relevant anatomies.

When necessary, Dr. Shafirstein’s laboratory will send the 3-D deidentified 
reconstruction models of the tumor anatomy and adjacent tissues to 
Simphotek Inc. for meshing. These files with meshes will be returned to Dr. 
Shafirstein’s laboratory at Roswell Park, for use in the DOSIE™ 
simulations. 
o
The 3-D model will be presented to the treating physician for review, and to indicate 
where fibers can be placed, including maximum depth and angles of insertion, 
relative to the surface of the airway. 
o
At Dr. Shafirstein’s laboratory, both DOSIE™ and COMSOL™ will be used to 
generate treatment planning for 630-nm laser. Each plan will use the same number and 
location of the fiber placement, diffuser length, and intensity (W/cm). The software 
packages will be used to compute the irradiance and fluence required to administer our 
target irradiance of ≥ 8.6 mW/cm2 in a significant volume of the target tumor. The plans 
will also suggest the treatment time to deliver ≥45 J/cm2 to a significant volume of the 
target tumor. 
o
For each plan, the research team will generate a table showing the light delivery options 
and percent of tumor volume that will receive the minimal and maximal irradiance and 
fluence for the physician to review.
o
The research team will compare the DOSIE™ computation with the COMSOL™. 
Although both use same input, the differences in the mesh generation and the solvers 
used in the simulations could impact the resulted irradiance and fluence. The 
comparison will include percent of tumor that receive ≥ 8.6 mW/cm2 and ≥ 45 J/cm2, 
the irradiance and fluence at the margins, the minimum, average, and maximum 
irradiance and fluence in 100% of the tumor. If there is disagreement (more than 5% 
difference) we will use COMSOL™ computation.

The treating physician will review the plan and either approve or request changes.
o
Several iterations (typically 1-3) may be required until the treating physician approves 
the plan. The review will be in-person or via secured web-based communication (e.g., 
password protected Microsoft Teams).   
o
Once approved, a detailed description of the plan will be provided via secured e-mail. 

The I-PDT procedure will follow the plan as much as possible, taking into consideration patient 
safety, and treatment time. 
o
Our previous studies suggest that fiber placement within ≤ 10 mm from the planned 
placement will have insignificant impact on the total light irradiance and fluence in the 
target tumor.
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o
The difference between the planned and actual placement of the fibers will be recorded 
(using EBUS imaging and measurements).  These data will be used for post analysis, 
to calculate the actual light distribution by DOSIE™ and COMSOL™.  
Extrabronchial tumors that are identified by EBUS will be treated with I-PDT. The laser fiber will 
be inserted into the tumor using the EBUS-TBN. The I-PDT procedure will follow these steps:

Curvilinear Endobronchial Ultrasound will be used to identify the tumor. 

The EBUS-color Doppler will be used to identify and locate the vasculature inside and 
adjacent to the tumor. 

EBUS guided transbronchial needle aspiration (Olympus America, Center Valley, PA) will 
be used to obtain tumor tissue specimen, prior to and after I-PDT. The specimen will be 
sent to cytology for analysis as per standard of care. Another specimen (tissue obtained 
prior to light delivery) will be sent to Dr. Shafirstein’s laboratory as described in Section 
8.2  below. The electronic health records (I) will be used to review and collect information 
from the cytology report.

In this study we will use fiber optics with cylindrical diffuser end that will be obtained 
from either Pinnacle Biologics Inc. Chicago, IL or Medlight SA, Ecublens, Switzerland. 
Both fibers will deliver same laser power output that will be checked and confirmed prior 
to treatment. The preference will be to use the Pinnacle fiber (Micro Diffuser Fiber 
that is the PB900 model) because it is stiff enough to be placed into the tumor through 
the 19 G EBUS needle (NA-201SX-4021; Olympus, Tokyo, Japan). This fiber will be 
provided at no cost to the study. 

In the event that the Pinnacle PB900 will not be available, we will continue to use the 
Medlight RD250 using a 19 G Cook endoscopic ultrasound needle (Cook Medical LLC, 
Bloomington, IN). The needle will be shortened to facilitate its use through an Olympus 
endobronchial ultrasound bronchoscope (Olympus America, Center Valley, PA). The 
shortened cook endoscopic ultrasound needle will only be used to deliver the PDT laser 
into the lesion. Shortening will be performed in the Roswell Park Laser Room. Once 
complete, the needle will be mounted on a specially designed laser fiber holding device.

The RD250 laser fiber preparation will be performed by inserting the laser fiber into a 
Progreat® Microsheath Catheter (Terumo Medical Corporation, Somerset, NJ). The 
microsheath catheter has a clear plastic distal end with Tungsten coil reinforcement. This 
laser/microsheath catheter will be inserted through the above mentioned shortened 
endoscopic ultrasound needle. The rationale for this is to provide sufficient stiffness to 
allow the laser fiber to be held in place within the lesion while the needle is withdrawn 
from the lesion. The laser power output (from the fiber/catheter end) will be checked and 
confirmed prior to treatment.

The laser fiber will be placed within the target tumor under EBUS guidance in one to 10 
locations, sequentially. The number and location of the fiber placement will be according 
to a pre-treatment planning (as much as possible), as the example shown in Figure 3.
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
If possible (i.e., optional), optical measurement of light transmission and tumor pO2 will 
be performed before and after I-PDT as described in section 1.1.13 

Using either fiber, a 630-nm laser light will be administered with the objective to deliver a 
minimal irradiance of ≥ 8.6, ≥ 10.8 or ≥ 15.3 mW/cm2 to a significant volume of the target 
tumor, based on Oakley et al. 2019. The treatment time will be adjusted to deliver ≥ 45 
J/cm2 to a significant volume of the target tumor. The research team will present a table 
showing the light delivery options and percent of tumor volume that will receive the 
minimal irradiance and fluence for the physician to review.

The pre-treatment plan will be presented to the treating physician (the investigator) for 
review and approval. The investigator will decide how many insertions will be made and 
where the fiber(s) will be inserted, using clinical judgment and taking into account the 
patient's safety.

The I-PDT procedure should be complete within a few hours.

Airway stenting will be performed after I-PDT, as needed. 
o
For cases where airway stenting is indicated to secure the airway, EBUS will be 
performed before or after airway stenting, as necessary, and the identified portion 
of the tumor will be evaluated and treated with I-PDT.
At least one tumor will be treated during the I-PDT. The treating physician will determine how 
many tumors will be treated, taking into account the patient’s safety.
6.1.3
Endobronchial tumors that are identified with endoscopy and prior CT or MRI will 
be treated with I-PDT and/or PDT

The laser fiber will be placed in the tumor for I-PDT or in the airway for PDT.

A 630-nm laser light will be administered with the objective to deliver a minimal irradiance of 
≥ 8.6, ≥ 10.8 or ≥ 15.3 mW/cm2 to a significant volume of the target tumor, based on Oakley 
et al. 2020. (41) The treatment time will be adjusted to deliver ≥ 45 J/cm2 to a significant 
volume of the target tumor. The research team will present a table showing the light delivery 
options and percent of tumor volume that will receive the minimal irradiance and fluence for 
the physician to review.

The pre-treatment plan will be presented to the treating physician (the investigator) for review 
and approval. The investigator will decide how many insertions or placements will be made 
and where the fiber(s) will be positioned, using clinical judgment and taking into account the 
patient's safety.

The I-PDT and/or PDT procedure/s should be complete within few hours.

Airway stenting will be performed after I-PDT and/or PDT, as needed.
o
For cases where airway stenting is indicated to secure the airway, EBUS will be 
performed before or after airway stenting, as necessary, and the identified portion of 
the tumor will be evaluated and treated with I-PDT and/or PDT.
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6.1.4 Criteria for Retreatment
Retreatments with porfimer sodium are allowed per the approved indication. The retreatments will 
take place at the discretion of the treating physician, if an incomplete response is observed, and 
the participant had no SAEs from the first I-PDT and/or PDT treatment. Since the porfimer sodium 
is retained in the disease tissue for at least 3-4 weeks, there is no need for additional drug 
administration. Therefore, the retreatment will consist of an additional light administration only.
6.1.5 Dose Modification/ Reduction
There will be no dose modification or reduction of the porfimer sodium. The light dose may be 
reduced, at the discretion of the treating physician, in the retreatment sessions.
6.1.6 General Concomitant Medication and Supportive Care
Withholding of anticoagulation and antiplatelet agents prior to bronchoscopy/I-PDT and/or PDT 
will be determined per investigator discretion and the anesthesia preoperative team, as per Roswell 
Park standard of care (e.g., warfarin for 5 days, clopidogrel for 5 days, etc.).
Participants may be pre-treated for nausea and vomiting with appropriate anti-emetics.
There is a potential for an exacerbation of skin photosensitivity if porfimer sodium is used with 
other photosensitizing drugs. No drug interactions have been investigated. 
The concomitant use of local anesthetics (infiltration anesthesia) is recommended and concomitant 
use of analgesics is also possible.
The use of antioxidants, including vitamin preparations, should be terminated on the day before 
treatment.
6.1.7 Precautions When Using Porfimer Sodium
Light-avoidance measures for approximately 30-90 days will be required. The clinical research 
coordinator and staff nurses will explain the light-avoidance measures to each subject, and a 
written instructions leaflet will be handed out to the subjects (Appendix B). The subject will be 
cautioned to protect the site of the infusion from excessive direct sunlight and certain bright lights 
for up to 3 months. The site may be exposed to normal ambient light.
Vital signs will be taken immediately after the end of the injection and 15 minutes after.
6.1.8 Duration of Treatment
The porfimer sodium photosensitizing drug will be given as a single dose 48 ± 4 hours (Day -2) 
before the EBUS I-PDT. The treatment is expected to be completed within a few hours.
6.1.9 Compliance
Any participant, who undergoes at least the EBUS-TBN guided I-PDT and/or I-PDT and/or PDT 
procedure and returns for the study follow-ups, is considered compliant when the treatment is 
administered.  
6.1.10 Risks and Benefits
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This is a Greater Than Minimal Risk study according to IRB criteria. Phototoxicity is the most 
likely potential risk associated with the systemic administration of the porfimer sodium. Proper 
shielding from the operating room lights will be maintained and the pulse oximetry sensor will be 
rotated every 20 – 30 minutes to minimize this risk. The subjects will be provided with written 
instructions on how to protect themselves from excessive light exposure.
The site-specific toxicity associated with this therapy includes:

Injection site reaction: Very common effects include pain at the injection site (12%) which 
is transient and can be minimized by slowing the injection rate. Common effects include 
injection site reaction (3%) and burning sensation (3%).

Tumor/local tissue reaction: Very common effects include pain (15%), hemorrhage (15%) 
and scarring (12%). Common effects include edema (8%), localized infection (8%), fever 
(8%), and skin necrosis (2%).

Phototoxicity: Common effects include sunburn (3%), blisters (5%), erythema (5%), 
hyper-pigmentation (3%), and cutaneous photosensitivity (3%).

Other systemic events: Constipation (11%), vomiting (9%), anemia (8%), nausea (6%), 
and giddiness (2%).
Potential Procedural Risks of EBUS-TBN Guided I-PDT and/or I-PDT and/or PDT

Bronchial bleeding from the insertion site 

Extension of the bronchoscopic procedure duration

Minimal risk of pneumothorax, infection, mediastinitis, allergic reaction to porfimer 
sodium

Airway perforation
Standard of care palliative radiotherapy followed by I-PDT.  It is not known what the risk 
is for administering the I-PDT two days after standard of care palliative radiotherapy. 
Potential Benefits of the Proposed Research
For participants that have partial or complete response to I-PDT and/or PDT, the potential benefits 
include a significant reduction in tumor mass and symptoms. There is no guarantee of the outcome, 
nor is it possible to predict whether or not any specific participant will respond to porfimer sodium 
I-PDT and/or PDT.
The data that will be collected in this study will allow the research team to evaluate the safety and 
provide indication on the potential efficacy of this treatment. If shown to be safe, we will use this 
data to design Phase I/II studies to confirm safety and test the efficacy of EBUS-TBN guided I-
PDT with porfimer sodium.
7
INVESTIGATIONAL PRODUCT
7.1.1
Active Substance and Source
The porfimer sodium for injection is supplied as a freeze-dried cake or powder as follows: NDC 
76128-155-75, 75 mg vial.
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7.1.2
Drug Shipment
Pinnacle Biologic, Inc. will ship porfimer sodium (Photofrin®) vials to Roswell Park to the 
Investigational Drug Service as per Roswell Park policy or to other enrolling study site. The 
receiving site will document the date of receipt and condition of the shipment. The investigational 
pharmacist or designee will retain drug shipment records.
The Photofrin® will be provided to the participants at no cost.
7.1.3
Preparation
Porfimer sodium will be prepared for injection following the manufacturer instructions: 
"Reconstitute each vial of porfimer sodium 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. Shake 
well until dissolved. Do not mix porfimer sodium with other drugs in the same solution. Porfimer 
sodium, reconstituted with 5% Dextrose Injection (USP) or with 0.9% Sodium Chloride Injection 
(USP), has a pH in the range of 7 to 8. Porfimer sodium 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 porfimer sodium is an opaque solution, in which detection 
of particulate matter by visual inspection is extremely difficult. Reconstituted porfimer sodium, 
however, like all parenteral drug products, should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit area from light.”
7.1.4
Storage and Stability
Porfimer sodium freeze-dried cake or powder will be stored at Controlled Room Temperature 20–
25°C (68–77°F). The porfimer sodium vials will be dispensed by the pharmacy of Roswell Park.
Documentation: A careful record of each vial dispensed (including lot number) will be maintained. 
This record will also include the date of drug administration and the patient ID for whom the drug 
was made available.
7.1.5
Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Pinnacle Biologics, Inc. exercising accepted medical and 
pharmaceutical practices. Study drugs must be handled as cytotoxic agents and appropriate 
precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the study staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
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Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
7.1.6
The Treatment Laser System
We will use one of the following laser systems for EBUS guided I-PDT 
1. An experimental medical PDT diode laser (ML7710-630-6W, Modulight Inc. Tampere, 
Finland). This system emits light with a wavelength of 630 ± 3 nm up to 6 Watts. The 
system includes a port for integrated light dose calibration unit. It is used under an IND 
from other studies (I 256814 and I 67918). 
2. The Modulight laser (ML7710-630, medical laser system, 630 ± 3 nm, 2 x 2.5 W (400 µm 
NA=0.22) individually controls laser fiber outputs with a SMA-905 connector and fiber 
sensors. It includes SMA-905 connector, fiber sensor, integrated dose calibration unit (for 
10-70 mm diffuser fibers), power control, dose calibration, and a foot pedal switch. This 
laser is used in protocol I 67918.
The Modulight's ML7710-PDT platform has been specifically designed for illumination in PDT 
treatment processes, to meet the requirements in dose calibration, power stability and wavelength 
tolerance. The ML7710-630 version designed specifically for porfimer sodium mediated PDT. It 
has CB certification and design documentation for CE/FDA. Modulight Inc. has CE 0537, 93/42 
EEC and ISO 13485 certifications to design and manufacture medical laser systems for PDT. 
These lasers are owned by Roswell Park:
3. A DIOMED 630 PDT Laser. This laser system emits 630 ± 3 nm up to 2 Watts. The FDA 
approved the use of this laser for PDT with porfimer sodium. Pinnacle Biologics Inc. 
provides this laser system at no cost to physicians that administer PDT with porfimer 
sodium. This service is offered for all customers including Roswell Park. The laser is 
shipped 1-2 days prior to the procedure. The laser safety officer inspects it prior to 
treatment. The laser is sent back (to Pinnacle Biologics) after treatment. This arrangement 
has been worked well for the past few years.
8
STUDY PROCEDURES
Informed consent MUST be completed prior to receiving any study related procedures.
Unless otherwise defined in the written protocol text, all procedures/assessments will be conducted 
in accordance with Roswell Park Clinical Research Services Standard Operating Procedures. 
8.1.1
Disease Evaluation
Patients with the diagnosis of lung cancer or other malignancies causing airway obstruction with 
and without involvement of the esophagus will be evaluated for enrollment in this study. 

Standard of care radiological imaging scans will be provided to the study team prior to 
EBUS-TBN I-PDT and/or I-PDT and/or PDT. These scans will be used for pre-treatment 
planning, with computer simulations of light propagation in the target tumor and margins.
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8.1.2
Baseline Evaluations
The following will be performed as standard of care procedures for the therapeutic bronchoscopy 
procedure within 4 weeks prior to scheduled I-PDT and/or PDT, unless otherwise indicated:

Medical history and pre-existing conditions (including type of lung cancer and all prior 
anti-tumoral therapy related to lung cancer)

Physical examination: including vital signs (i.e., temperature, heart rate, respiratory 
rate, blood pressure), body weight, and height

Hematology: Complete blood count (CBC) with automated differentials (routinely 
performed before bronchoscopy under general anesthesia in all cases). CBC  with 
automated differentials includes: WBC, RBC, HGB, HCT, platelet, MCV, MCH, 
MCHC, % neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % 
eosinophils, absolute eosinophils, % basophils, absolute basophils, % lymphocyte, 
absolute lymphocyte, platelet confirmation (as clinically indicated), and differential 
confirmation (as clinically indicated).

Chemistry: Complete metabolic panel (CMP) (routinely performed before 
bronchoscopy and general anesthesia in all cases). CMP includes: chloride, CO2, 
potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total 
bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol 
(Calc), anion gap.

Pregnancy test (urine or serum HCG will be obtained if urine is not available) in 
females of childbearing potential: to be performed within 7 days prior to treatment. 
Females who have undergone surgical sterilization or, who have been postmenopausal 
for at least 2 years are not considered to be of childbearing potential. The standard 
operating procedure for all females of childbearing potential in the Ambulatory 
Surgical Center (ASC) pre-op holding area is to obtain a urine HCG (or a serum HCG 
if urine is unable to be obtained). As per standard of care procedures, if the pregnancy 
test is positive, the patient is excluded from the study.

ECOG Performance Status (Appendix A)

Quality of Life Questionnaire (Cohorts A and, B): Quality of life will be assessed using 
the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale.  The 36 self-
report items on the FACT-L measure six domains of quality of life (physical well-
being, social/family well-being, relationship with doctor, emotional well-being, 
functional well-being, and additional concerns).  FACT-L is written at a sixth grade 
reading level and takes an average of 7 minutes to complete. It is based upon recall 
over the last seven days of time. FACT-L was chosen because multiple studies support 
its validity and use in clinical trials of lung cancer (73, 74, 88, 89). It has been used 
across Phase 1-Phase 3 clinical trials. Additionally, prior research has quantified the 
minimal clinically important difference, and has been used to distinguish complete 
responders from non-responders in other studies (54). Study subjects will be given the 
questionnaire (see Appendix D) at time of study enrollment and at each follow up visit 
until study completion via tablet (or paper questionnaire if tablets are unavailable at 
that time). 
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
Six-Minute Walk Test (Cohorts A and  B): The Six-Minute Walk Test is the most used 
measure of functional capacity in lung cancer (55, 70). As the pathophysiology of 
central airflow obstruction is similar regardless of the underlying malignancy, authors 
have evaluated change in 6-minute walk distance across a range of malignancies, 
including sarcomas, breast, colon, esophageal, and thyroid cancers (71). Additionally, 
the effect of treatment will hopefully be evident in differences in exercise tolerance, 
oxygen saturation, and dyspnea. 

Tumor/Disease Assessment: Chest CT scan - to be performed within 2 weeks ± 1 week 
treatment. These CT scans will be used for the pre-treatment planning.

Concomitant Medications: List any current medications taken within 1 week of study 
treatment.
8.1.3
Days Prior to the EBUS Guided I-PDT Procedure 

All participants will have a blood draw for CBC with automated differentials and CMP 
within 2 days prior to administration of porfimer sodium.  Additionally, patients on 
chemotherapy will have a blood draw within 2 days for CBC and CMP prior to PDT.

For all participants: systemic administration of 2 mg/kg porfimer sodium 48 ± 4 hours 
(Day -2) prior to I-PDT as described in Section 6.1.1.

Blood draw for immune biomarkers prior to the administration of the porfimer sodium.

For Cohort B participants only: standard of care palliative radiotherapy of 8 Gyx1 will 
be administered to the target tumor at day -2 just before systemic administration of 
2 mg/kg porfimer sodium. This will be coordinated with the radiation oncologist. 
8.1.4
Evaluations Performed on Day of EBUS guided I-PDT Procedure (Day 0)

On the day of the EBUS guided I-PDT procedure (Day 0), all participants will start fasting 
at midnight per current recommended preparation for the procedure. Participants are 
allowed to resume their diet after the procedure (according to the standard clinical 
instructions).  

Physical examination including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure) and oxygen saturation, as per SOC. Note: on the day of scheduled 
bronchoscopy, weight is not needed at the preoperative and postoperative physical 
exam.
Note: Pre- and post-op physical is required (even if there has been an exam within 30 days 
prior to procedure). Because of the acuity and severity typical to this particular patient 
population, patients require a physical pre- and post-surgical intervention.

Review of Concomitant Medication

Tumor debulking, ablation, or stenting (as part of standard of care for therapeutic 
bronchoscopy)

I-PDT and/or PDT using standard endoscopy to guide the therapy. 

Tumor/disease assessment by bronchoscopy with endobronchial ultrasound-guided 
transbronchial needle aspiration (EBUS-TBNA). 
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
EBUS-color Doppler to identify vasculature.

From the EBUS 1 to 5 biopsies are collected prior to I-PDT for drug uptake. See Section 
8.2 for testing and processing details. 

From the EBUS 1 to 5 biopsies are collected prior to I-PDT for immune markers. See 
section 8.11 for testing and processing details.

If possible, take optical measurements and tumor pO2 immediately before and after 
EBUS I-PDT.  

EBUS-TBN guided I-PDT 

From the EBUS 1 to 5 tumor tissue biopsies are collected from the treated 
area immediately (within minutes) after I-PDT.  See Section 8.3 for testing and 
processing details.

Immune marker blood sampling:  Day of EBUS-TBN guided I-PDT and/or I-PDT 
and/or PDT prior to laser light illumination
The following evaluations will be performed on the same day following bronchoscopy/EBUS-
TBN procedure:

Physical examination (including vital signs), oxygen saturation

Adverse events
8.1.5
EBUS-TBN guided I-PDT and/or I-PDT and/or PDT
Day of scheduled bronchoscopy (Day 0):

I-PDT will be administered with a 630±3 nm laser light that will be delivered through 
optical laser fiber with cylindrical diffuser end.

The EBUS will be used to image the insertion of the laser fiber into the tumor prior to 
treatment, and changes in blood flow and volume during treatment.

The endoscope will be used to guide the fiber location when I-PDT and/or PDT will be 
used to treat the target tumor.

All patients will undergo an interventional bronchoscopy procedure with an attempt to 
treat and resolve the airway obstruction using conventional methods such as balloon 
dilation, mechanical debulking, tumor ablation and/ or airway stenting. Airway stenting 
will be performed before or after I-PDT and/or PDT, if deemed necessary.

1 to 5 tumor tissue biopsies are collected from the treated area immediately (within 
minutes) after EBUS.
8.1.6
Days Post EBUS Guided I-PDT Procedure

For Cohorts A and B, standard of care bronchoscopy will be performed if clinically 
indicated at 48 ± 4 h post therapy.  If additional I-PDT will be conducted, optical 
measurements will be performed before and after I-PDT.
8.1.7
7 – 10 Days Post-Procedure

Blood draw for immune biomarkers
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8.1.8
Initial Follow-Up Evaluation
The following evaluations will be performed 4 weeks (± 1 week) after the last study I-PDT and/or 
PDT (unless otherwise indicated*):

Physical examination (including vital signs)

Hematology: Complete blood count (CBC) with automated differentials.

Chemistry: Complete metabolic panel (CMP).

Blood draw for immune markers

ECOG Performance Status (Appendix A)

Tumor/Disease Assessment: Chest CT scan

Concomitant medications

Quality of Life Questionnaire (Cohorts A and B; Appendix D) 

Adverse events (will be followed for 30 days following treatment/procedure)

Schedule date/time for follow-up bronchoscopy with EBUS (without TBNA). TBNA 
will be performed only if clinically indicated outside the scope of this study. If a tumor 
is visible, tumor tissue biopsies (about 50-300 mg per biopsy, if feasible) will be 
collected for immune markers. NOTE: The bronchoscopy will not be performed at this 
visit.

If EBUS is performed and a tumor is visible, tumor tissue biopsies (about 50-300 mg 
per biopsy, if feasible) will be collected for immune markers.
*Bronchoscopic and ultrasound images that are routinely obtained during therapeutic procedures 
will be used to evaluate the airway initially and during follow up. Note: Initial follow-up 
bronchoscopy will be performed within 4 weeks following the first follow-up visit. Additional 
bronchoscopies will be performed as clinically indicated.
8.1.9
Long Term Follow-Up Evaluations
The following evaluations will be performed at 8 weeks (± 2 weeks), 12 weeks (± 2 weeks) and 
24 weeks (± 4 weeks) after last study I-PDT and/or PDT (or when clinically indicated):
Physical examination (including vital signs)
ECOG Performance Status (Appendix A)
Concomitant medications: Required as indicated throughout the long-term follow-up period so 
that any medications that may interfere with immune function are documented.
Chest CT scan
Quality of Life Questionnaire at 12 and 24 weeks (Cohorts A and B; Appendix D) 
Six-Minute Walk Test at 12 weeks and 24 weeks (Cohorts A and B) 
8.1.10 Patients coming off the study:

Patients will be taken off the study and no data will be collected after the follow-up visit at 
24 weeks (± 4 weeks) after the last I-PDT and/or PDT.
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
All patients, including those that progress prior to 24 weeks, will continue to be followed 
for disease and survival status for the full 24 weeks.
Progression of disease will not cause the patients to be off study. We will continue to collect 
response data as it will be part of standard of care for these patients. We will use modified RECIST 
1.1 to determine response. 
8.1.11 Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Table 1 below.
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Table 1
Schedule of Procedures and Observations
Evaluation
Baseline1
Day 
-3
Day 
-2
Day -1
Scheduled 
EBUS I-
PDT 
(Day 0)
Days 1 
through 3
Days 
2 through 
1022
7-10 Days 
Post-
Procedure
Initial 
Follow-Up2 
Evaluation
Long Term 
Follow-Up3
Evaluation
s
Medical History
X
Pre-Existing Conditions
X
Physical Examination, 
including vital signs4
X
X5
X5,22b
X
X
Hematology6
X
X24
X24
X
Blood Chemistry/creatinine 
clearance7
X
X24
X24
X
Pregnancy Test (Urine/Serum)
X8
ECOG Performance Status 
(Appendix A)
X
X
X
Tumor/Disease Assessment: 
Contrast Enhanced CT scan 
(chest) 9 (non-contrast CT if the 
patient has allergy to the 
contrast agent) 
X9
X9
X9
Injection of porfimer sodium
X
Diet prior to I-PDT procedure
X20
X20a
Cohort B Only: SOC palliative 
radiotherapy 
X22
SOC Bronchoscopy/EBUS-
TBNA
X10
X11
EBUS color Doppler to identify 
vasculature
X
Tumor Debulking, Ablation 
and/or Airway Stenting
X
X


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Evaluation
Baseline1
Day 
-3
Day 
-2
Day -1
Scheduled 
EBUS I-
PDT 
(Day 0)
Days 1 
through 3
Days 
2 through 
1022
7-10 Days 
Post-
Procedure
Initial 
Follow-Up2 
Evaluation
Long Term 
Follow-Up3
Evaluation
s
If possible, optical and pO2 
measurements immediately 
before and after I-PDT
X23
I-PDT 12 guided with EBUS-
TBN and/or I-PDT and/or PDT
X
Immune marker blood and 
tumor tissue sampling13 
X
X
X
X
Pre-I-PDT and/or PDT tissue 
sample
X14,14a
X14b
X14
Concomitant Medications
X15
X
X22b
X
X16
Adverse Events
X
X22b
X
Quality of Life Questionnaire 
(Appendix D)17
X
X
X18
Six-Minute Walk Test21
X
X18
Survival Status
X19
1
Performed within 4 weeks prior to scheduled EBUS I-PDT, as part of standard of care for the therapeutic bronchoscopy, unless otherwise indicated.
2
Initial Follow-Up evaluation at 4 ± 1 weeks after the last I-PDT and/or PDT treatment (dependent on severity of disease and clinical condition of patient).
3
Long-Term Follow-Up routine will be performed only when clinically indicated, at these visits: 8 weeks (± 2 weeks), 12 weeks (± 2 weeks), and 24 weeks (± 4 weeks) 
after the last I-PDT and/or PDT.
4
Vital signs: temperature, heart rate, respiratory rate, blood pressure, body weight, and height. Height collected at baseline only.
5
To be performed prior to procedures as SOC and at post-operative evaluation after undergoing treatment. Note: on the day of scheduled bronchoscopy, weight is not 
needed at the preoperative and postoperative physical exam. Oxygen saturation to be measured pre- and post-operatively.
6
Standard of care - will be performed if indicated by the anesthesia pre-op assessment: Complete blood count (CBC) with automated differentials: WBC, RBC, HGB, 
HCT, platelet, MCV, MCH, MCHC, % neutrophils, absolute neutrophils, % monocytes, absolute monocytes, % eosinophils, absolute eosinophils, % basophils, absolute 
basophils, % lymphocyte, absolute lymphocyte, platelet confirmation (as clinically indicated), and differential confirmation (as clinically indicated).
7
Standard of care - will be performed if indicated by the anesthesia pre-op assessment: Complete metabolic panel (CMP): chloride, CO2, potassium, sodium, BUN, 
glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap.
8
Within 7 days prior to study treatment. Serum HCG will be obtained if urine is not available.


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9
CT scan will be within 2 weeks ± 1 week prior to study treatment.  CT scan in Follow-Up, will be performed only when clinically indicated, at these visits: 4 weeks (±1 
week), 8 weeks (± 2 weeks), 12 weeks (± 2 weeks), and 24 weeks (± 4 weeks) after the last I-PDT and/or PDT.
10
Bronchoscopy (SOC) with EBUS-TBNA. The details of the interventional bronchoscopy procedure described in Section 6.1.2 are standard of care and, do not need to be 
documented in the Case Report form.
11
Schedule date/time for initial follow-up SOC bronchoscopy without EBUS-TBNA: TBNA will be performed only if clinically indicated outside the scope of this study. 
Note: Initial follow-up bronchoscopy will be performed within 4 weeks following the initial follow-up visit.
12
I-PDT and/or PDT will be performed with 630-nm light delivered through a cylindrical diffuser that will be inserted into tumor through a TBN with EBUS guided 
imaging. Endobronchial tumors can be treated with I-PDT and/or PDT. An endoscope will be used to guide the fiber placement.
13
Refer to Section 8.12
14
Refer to Section 8.13 for standard of care Pathology procedures. 
14a.Tissue is taken before and after I-PDT during the EBUS I-PDT. For the Tissue Immune Markers and Drug Uptake processing, tissue is taken prior to EBUS I-PDT, 
see Section 8.4. For the Tissue Sample for the STAT3 Crosslinking processing, tumor tissue is collected from the treated area immediately (within minutes) after EBUS  
I-PDT procedures, see Section 8.3
15
Required as indicated throughout the long-term follow-up period so that any medications that may interfere with immune function are documented.
16
List any ongoing medications with an onset within 1 week of study treatment.
17
Survey data will be stored in REDCap.  Quality of Life Questionnaires do not apply to Cohort 0 participants.
18
Only required at 12 and 24 weeks.
19
For all patients, (including those with disease progression prior to 24 weeks), survival status will continue to be collected until 24 weeks. After 24 weeks they will come 
off study.
20
For day of EBUS I-PDT bronchoscopy (Day 0), starting at midnight, all participants are fasting at home per normal preparation procedures.  Participants can eat after the 
procedure (according to the standard clinical instructions).  
21
The Six Minute Walk Test does not apply to Cohort 0 participants.
22
Palliative radiotherapy of 8 Gyx1 will be administered to the target tumor at day -2 just before systemic administration of 2 mg/kg porfimer sodium. This will be 
coordinated with the radiation oncologist. This only applies to participants in Cohort B. 
23
Optical measurements and tumor pO2 will be conducted as described in section 1.1.13, optional. The data will be saved on password secured computer in Dr. Shafirstein 
laboratory. The CRF will only document that these measurements were done.  
24
All participants will have a blood draw for CBC and CMP within 2 days prior to administration of porfimer sodium.  Additionally, patients on chemotherapy will have a 
blood draw for CBC and CMP within 2 days prior to PDT.
If there are multiple PDT treatments for patients on  chemotherapy, CBC and CMP will be done within 2 days prior to each treatment.


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8.2
Tissue Sample for Drug Uptake and Immune Markers
If possible, before I-PDT and/or PDT, tissue samples (about 100-300 mg per biopsy if feasible) 
from the primary lung tumor (or other tumor to be treated) will be collected intraoperatively for  
measurement of optical properties and porfimer sodium concentration levels prior to light delivery 
(EBUS I-PDT).
These tissue samples will be sent from the operating room via the Clinical Research Laboratory 
Services to Dr. Shafirstein’s laboratory in the Roswell Park PDT center, even for procedures 
performed after hours. The specimens will be labeled with the subject’s MR number, initials, study 
number, protocol time point, dose, and protocol day.
Note: PDT center laboratory personnel will be notified by tissue procurement when the sample is 
available for pick-up. Tissue is to be wrapped in an opaque, sterile surgical towel, placed in a 
biosafety bag and transported on ice to Dr. Shafirstein’s laboratory.
Samples will immediately be frozen at -70oC until analyzed. Samples will be processed, stored 
and analyzed in Dr. Shafirstein’s laboratory:
Gal Shafirstein, D.Sc.
Roswell Park Comprehensive Cancer Center PDT Center
Medical Research Complex (MRC) M-156
Attn: Study Number I 279415
Elm & Carlton Streets
Buffalo, NY 14263
Office phone: 716-845-4025
Laboratory phone: 716-845-4893
Off hours contact number (cell): 716-698 0467
Gal.Shafirstein@RoswellPark.org
EXTERNAL (NETWORK) SITES: Follow directions above for sample collection and 
processing (Note: External sites will process samples as personnel will be cross trained for uniform 
sample processing.). The cryogenic tubes will be labeled with the Subject ID #, initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day. 
The samples will immediately be frozen at -70ºC or below (samples are to be stored until requested 
for batch mailing). Samples are to be batch shipped, frozen, on dry ice. 
Roswell Park External Site Coordinators must be notified by email on the day prior to sample 
shipment at CRS-QA@RoswellPark.org.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon.-Fri., 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments to the address provided above. For any questions regarding specimen 
processing contact Dr. Gal Shafirstein, (716)-845-4025 or email: 
Gal.Shafirstein@RoswellPark.org.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
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in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
Porfimer sodium levels in tissues will be monitored using a fluorescence assay because of the high 
quantum fluorescence yield of the drug and the inherent increased sensitivity of 
spectrofluorometry 
over 
absorption-based 
methods 
(e.g., 
spectrophotometry, 
HPLC). 
Concentrations of porfimer sodium will be determined by admixture with SolvableTM (Packard 
Bioscience, Meriden, CT) and heating at 53oC followed by analysis of fluorescence emission 
spectra. Briefly, following treatment with Solvable™ and heat, each sample will be placed in a 
quartz cuvette and a fluorescence emission spectrum (λex = 412 nm) will be obtained using a 
commercial fluorometer. If sufficient sample is available, 2 - 3 replicate determinations of 
porfimer sodium concentration will be obtained. The amplitude of the fluorescence emission 
maximum (λem = 670 nm), following baseline correction, will be compared to a standard curve 
obtained by processing known amounts of porfimer sodium in SolvableTM.
8.3
Tissue Sample for STAT3 Crosslinking
If possible, we would like to quantify the photoreaction using an assay that will evaluate the signal 
transducer and activator of transcription 3 (STAT3) crosslinking that we have shown to be 
associated with durable response of early stage HNSCC treated with external beam PDT (1). For 
performing the STAT3 assay, the treating physicians will use the EBUS  (if performed as well) to 
collect 1 to 5 tumor tissue biopsies (about 100-300 mg per biopsy, if feasible) from the treated 
area immediately (within minutes) after I-PDT. These research biopsies will be snap-frozen on 
dry ice and processed for determining STAT3 cross-linking as previously described (2, 3). 
Immunoblot signals for STAT3 will be quantified and expressed as percent conversion of 
monomeric into covalently cross-linked dimeric STAT3.  
Samples will immediately be frozen at -70oC until analyzed. Samples will be processed, stored, 
and analyzed in Dr. Shafirstein’s laboratory (same location). 
Dr. Gal Shafirstein, D.Sc.  
Roswell Park Comprehensive Cancer Center PDT Center
Medical Research Complex (MRC) M-156
Attn: Study Number I 279415
Elm & Carlton Streets
Buffalo, NY 14263
Office phone: 716 845-4025 
Off hours contact number (cell): 716 698-0467 
Gal.Shafirstein@RoswellPark.org
EXTERNAL (NETWORK) SITES: Follow directions above for sample collection and 
processing (Note: External sites will process samples as personnel will be cross trained for uniform 
sample processing.). The cryogenic tubes will be labeled with the Subject ID #, initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day. 
The samples will immediately be frozen at -70ºC or below (samples are to be stored until requested 
for batch mailing). Samples are to be batch shipped, frozen, on dry ice. 
Roswell Park External Site Coordinators must be notified by email on the day prior to sample 
shipment at CRS-QA@RoswellPark.org.
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Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon.-Fri., 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments to the address provided above. For any questions regarding specimen 
processing contact Dr. Gal Shafirstein, (716-845-4025) or email: 
Gal.Shafirstein@RoswellPark.org.  
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.4
Blood Draw and Tissue Samples for Immune Markers
Recent work from the Gollnick lab has demonstrated the critical role of the immune system in 
PDT efficacy. Because of the importance of the immune system for PDT efficacy, along with the 
potential for the immune system to mount an effective anti-tumor response, it would be beneficial 
to monitor immune markers (detailed in the last paragraph of Section 1.9) for correlation between 
the I-PDT and/or PDT treatment and local or distant disease recurrence.
Blood samples will be collected via venipuncture for immune marker analysis. Samples will be 
collected using 3, 10 mL heparinized green-top collection tubes. Tumor tissue samples (50-300 
mg per biopsy) will be collected during the endoscopy procedure using the EBUS needle. 
Samples for immune marker analysis will be obtained on:

Blood samples prior to the administration of the porfimer sodium and on the day of 
porfimer sodium administration.  

Tumor tissue and blood sample prior to the laser light illumination and on the day of I-PDT 
and/or PDT. 

7-10 days following I-PDT and/or PDT with bronchoscopy procedure.

Initial follow-up (approximately 4 weeks ± 1 week following last I-PDT and/or PDT with 
bronchoscopy)
Whole blood samples (3 tubes) and fresh tissue samples (in saline) will be sent the same day of 
collection, to the Flow Cytometry Department for processing. 
Joseph Tario, PhD
Department of Flow and Image Cytometry
Cancer Cell Center C-311
Attn: Study Number I 279415
Elm & Carlton Streets
Buffalo, NY 14263
Office phone: 716-845-8418
Laboratory fax: 716-845-8806
flowlab@RoswellPark.org
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EXTERNAL (NETWORK) SITES: Follow directions above for sample collection and 
processing (Note: External sites will process samples as personnel will be cross trained for uniform 
sample processing.). The cryogenic tubes will be labeled with the Subject ID #, initials, the 
participant’s study number, clinical study number, protocol time point, dose, and protocol day. 
The samples will immediately be frozen at -80ºC or below (samples are to be stored until requested 
for batch mailing). Samples are to be batch shipped, frozen, on dry ice. 
Roswell Park External Site Coordinators must be notified by email on the day prior to sample 
shipment at CRS-QA@RoswellPark.org.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon.-Fri., 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments to the address provided above. For any questions regarding specimen 
processing contact Dr. Joseph Tario, (716)-845-8418 or email:  flowlab@RoswellPark.org.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8.4.1
Pathology
Standard pathologic analysis of resected lung tissue will be performed. The electronic health 
records (EHR) will be used to review and collect information from the cytology report.
9
EFFICACY EVALUATIONS
9.1
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion at baseline and during 
follow-up. A modified RECIST 1.1 criterion will be used to assess objective tumor response of 
the I-PDT and/or PDT treated tumor.
RECIST 1.1 will be used for tumor response assessment at time of continuing review and will be 
used for IRB reporting and formal analysis.
Along with tumor size and volume, percent of airway obstruction (in cases where an airway stent 
is not placed) measured by bronchoscopy, will also be used as a measure of tumor response.
9.2
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, will be identified as target lesions and recorded and measured at baseline. 
Target lesions will be selected on the basis of their size. Lesions with the longest diameter (short 
axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph nodes, > 20 mm CXR and 
are for accurate repetitive measurements (either by imaging techniques or clinically) will be 
chosen. A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
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calculated and reported as the baseline sum diameters. This will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease.
The above standard RECIST technique will be used for measurement of the longest diameter of 
the target lesion.
NOTE: We will use I-PDT and PDT to treat extrabronchial and endobronchial tumors. The 
extrabronchial will be treated with EBUS-TBN I-PDT. The endobronchial tumors (inside the 
airway) can be treated with I-PDT and/or PDT. All treated tumors will be measured by CT scans 
(baseline and follow-up).
Tumors that are inside the airway that will be treated with laser, rigid bronchoscopy or ablation 
(see Section 6), will not be measured on CT scan.
Therefore, the volume of the tumor that will be treated with either EBUS-TBN I-PDT or with I-
PDT and/or PDT will be measured on CT that was performed within 2 weeks ± 1 week before the 
procedure (refer to Section 8.1: Baseline Evaluations) will be compared to the volume of the I-
PDT and PDT treated tumor on CT that is taken at initial follow-up bronchoscopy (refer to Section 
8.1.5).
9.2.1
Evaluation of Target Lesions
Tumor response assessments will be performed at 4 weeks (± 1week) following I-PDT and/or PDT 
(refer to Section 8.1.8).

Complete Response (CR): Disappearance of all target lesions.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.

Stable Disease (SD): Neither a sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameter while on study.
9.2.2
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.

Contrast-Enhanced CT: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
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the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
Non-contrast CT can be used if the patient has allegory to the contrast agent.

Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
9.2.3
Evaluation of Airway Obstruction
The estimated percentage of obstruction will be documented before and after endobronchial 
debulking and ablation. Tumor debulking and ablation will always be performed before EBUS-
TBNA. The airway obstruction severity is usually estimated based on the size of scope that can be 
passed through an obstructed airway and based on the size of the balloon used to dilate the 
obstructed airway.
Airway obstruction severity will be classified as follows (51):

Mild (<50%),

Moderate (50-70%) and,

Severe (>70%). 

The baseline obstruction to be used in the study will be the airway obstruction that was 
established after debulking and ablation and, before the EBUS-TBN guided I-PDT, 
and/or I-PDT and/or PDT.
9.2.4
Progression-Free Survival
PFS, using modified RECIST 1.1 criteria, is defined in this study as the time from date of study 
treatment to the time of first observed disease progression at the treated tumor site or, death due to 
any cause.
10 SAFETY EVALUATION
Adverse Events
10.1.1 Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
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10.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
10.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
10.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
10.1.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
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10.1.2 Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 5 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 5 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology and documented according to the grading scales provided in the CTCAE Version 5.0.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the 
participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was 
most likely related to other factors such as the participant’s clinical state, other 
therapeutic interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration and follows a known response pattern to the study drug. The event 
cannot be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be 
reasonably explained by other factors such as the participant’s condition, therapeutic 
interventions or concomitant drugs; AND occurs immediately following study drug 
administration, improves upon stopping the drug, or reappears on re-exposure.
10.1.3 Reporting Adverse Events
Table 2 
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
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Adverse events will be graded from 1 to 5. Mild and moderate side effects are common after 
therapeutic bronchoscopy for central airway tumors. Therefore, grade 3 or above will be included 
in safety analysis, and grades 1 and 2 will be collected and reported.
Serious Adverse Events
10.1.4 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from 
the reaction as it occurred. It does NOT include an AE that, had it occurred in a more 
severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize 
the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
10.1.5 Reporting Serious Adverse Events
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
principal investigator or designee will inform Roswell (via email using both the Oncore SAE form 
and MEDWATCH 3500A form) within twenty-four (24) hours of first awareness of any event that 
meets the above criteria. Forms will be submitted to SafetyEventReporting@RoswellPark.org. See 
Appendix C for Multi-site reporting instructions. SAEs occurring after the 30 day follow-up period 
that the investigator determines to be possibly, probably or definitely related to the study 
intervention should be reported.
SAEs that are unexpected and possibly, probably or definitely related must be reported as an 
Unanticipated Problem. Please refer to Section 0 for details on reporting Unanticipated Problems.
Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
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Unanticipated Problems
10.1.6 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data.
o
The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized or if in relation to an AE is deemed Serious per Section 0.
10.1.7 Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. The Reportable New 
Information Form will be submitted to the CRS Quality Assurance (QA) Office within 1 business 
day of becoming aware of the Unanticipated Problem. After review, the CRS QA Office will 
submit the RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
11 DATA AND SAFETY MONITORING
The Roswell Park Data and Safety Monitoring Committee (DSMC) will assess the progress of the 
study, the safety data, and critical efficacy endpoints. The DSMC will review the study annually 
and will make recommendations that include but not limited to; (a) continuation of the study, (b) 
modifications to the design, (c) suspension of or, (d) termination of the study.
12 STATISTICAL METHODOLOGY
This is a multi-center, multi-arm, Phase I (Cohort 0, data collection completed) and  Phase II 
study [Cohort A (8 already enrolled under Phase 1 portion of Cohort A from previous protocol 
version) and Cohort B]. Cohort 0 is closed to accrual and fulfilled the Phase 1 safety monitoring 
requirements. Cohort 0 provided the safety monitoring component for Cohort A of this Phase II 
study. Cohort 0 consisted of patients with the diagnosis of lung cancer that received porfimer 
sodium with EBUS I-PDT and all of the study procedures with the exception of the Quality of 
Life Questionnaires and Six Minute Walk Test.  Cohort A consists of patients with the diagnosis 
of lung cancer or other malignancies causing airway obstruction, or cancer that is not a candidate 
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for surgery or curative radiation therapy; EBUS I-PDT; and all of the study procedures.  Cohort 
B will consist of patients with the diagnosis of lung cancer or other malignancies causing airway 
obstruction, or cancer that is not a candidate for surgery or curative radiation therapy. Subjects in 
Cohort B will receive the EBUS guided I-PDT 48±4 h after standard of care palliative 
radiotherapy of 8 Gy x1.
The primary safety endpoints for Cohort 0 for this study are:

AEs that are ≥ Grade 4.
The primary efficacy endpoints for Cohort A and  Cohort B portion of this study are:

Objective tumor response (CR, PR, PD, and SD)

The FACT-L Total Score related subscale

6-Minute walk measures
The secondary endpoints for Cohort 0+A and Cohort B of this study are:

The number of bronchoscopies

Progression free survival

Compare the treatment plan in DOSIE™ with the plan generated in COMSOL™ in 
Cohort A only. 

Measure changes in optical properties and irradiance and fluence and relationship to 
response. 
The exploratory endpoints are for Cohort 0+A and Cohort B of this study: 

Porfimer sodium retention in the target tumor tissue

The relationship between immune biomarkers and response
12.1.1 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, minimum, and maximum) will be 
used to summarize demographic and baseline characteristics.
12.1.2 Primary Cohort 0 Phase I Safety Analysis
For patients LALC or other malignancies in the central airway that may extend and involve the 
esophagus.  For Cohort 0, the safety profile will be measured by recording I-PDT and/or PDT 
treatment related AEs that are ≥ grade 4 with attribution of ‘possible’, ‘probable’, or ‘definite’, 
according to the NCI CTCAE v5.0. The safety measures will be evaluated in all patients who 
received I-PDT and/or PDT following bronchoscopic intervention for malignant airway 
obstruction. Let  represent the proportion of the evaluable population of interest who experience 
𝑝
an AE≥ grade 4. A true response of more than 
=0.20 is considered unacceptable and evidence 
𝑝0
of such will deem the treatment unsafe for further study.
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The null and alternative hypotheses to be tested are:
0
0
0
:
,
:
.
a
H
p
p
H
p
p


The study design stops early for evidence of safety and will proceed in two stages:

Stage 1: If 0 out of the first 3 evaluable participants have an I-PDT and/or PDT treatment 
related AE≥ grade 4 (with attribution of ‘possible’, ‘probable’, or ‘definite’), it will be 
concluded that the therapy is safe and the study will enter the Phase II component. 
Otherwise, the study will progress to the second stage.

Stage 2: We will accrue 3 additional evaluable participants. If 3 or more of the total of 6 
evaluable participants will have I-PDT and/or PDT treatment related AE≥ grade 4 
(attribution of ‘possible’, ‘probable’, or ‘definite’), it will be concluded that  exceeds 
𝑝
and that the therapy is unsafe; otherwise, it will be concluded that the therapy is safe and 
enter the Phase II component.
The nominal significance level of this design is α=0.10.
12.1.3 Primary Phase II Efficacy Analysis
The primary endpoint for Cohort A and Cohort B is the proportion of complete responders (CR) 
and partial responders (PR) as measured by RECIST v1.1 at 12±1 week after DOSIE™ (Cohort 
A) and COMSOL™ guided I-PDT.  
For Cohort A, we hypothesize that the objective tumor response for CR+PR will be at least 29%. 
We also want to investigate the impact of variation in optical properties, Photofrin® retention, 
and fiber location perturbation on the objective tumor response.  The primary analysis will 
consist of a one-sided exact binomial test of H0: π=0.05 versus Ha: π>0.05 at level α=0.05, where 
π is the proportion of CR+PR responders. For Cohort B, the primary analysis will consist of a 
one-sided exact binomial test of H0: π=0.30 versus Ha: π>0.30 at level α=0.05.  
 Additional clinical efficacy endpoints are: (1) changes from baseline to 3 months in the FACT-L 
Total Score related subscales (physical well-being, social/family well-being, emotional well-
being, functional well-being); (2) the 6-minute walk measures (distance, VO2max, shortness of 
breath scores).  All key clinical efficacy outcomes will be considered suitably continuous will be 
analyzed with an analysis-of-covariance (ANCOVA) approach regressing change from baseline 
to three months on the baseline value of the respective measure adjusted for baseline tumor 
volume, age, and sex.
12.1.4 Secondary Analysis
For both Cohort 0+A combined and Cohort B progression free survival (PFS) will be defined as 
the time from date of study treatment to the time of first observed disease progression (modified 
RECIST 1.1 criteria) at the treated tumor site or death due to any cause. PFS will be summarized 
using standard Kaplan-Meier methods, with median PFS and specified PFS rates estimated with 
95% confidence intervals.  The number of bronchoscopies will be summarized descriptively. 
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For Cohort A only we will measure agreement between DOSIE™ and COMSOL™ treatment 
planning measures in n=18 subjects consisting of light intensity from each fiber (mW, and 
mW/cm), percent of tumor that receives ≥8.6 mW/cm2 and ≥45 J/cm2, the irradiance and fluence 
at the margins, the min, average and maximum irradiance and fluence in 100% of the tumor using 
the concordance correlation coefficient (76)(CCC) and Bland-Altman plots (77) for visual displays 
of agreement. We will calculate the one-sided 95% confidence interval for the CCC using a 
percentile bootstrap-t approach for each endpoint and we will calculate the 95% confidence 
interval for the paired differences relative to the Bland-Altman graphical display. Disagreement 
on a given measure will be inferred if the estimated CCC is below the lower bound of the one-
sided 95% percentile confidence interval. 
Tumor response as a function of STAT3 tumor conversion percentages (if possible) will be 
analyzed using logistic regression adjusted for age and sex.
The data from this trial will inform the design of a prospective Phase IIb randomized trial. 
12.1.5 Exploratory Analysis
Porfimer sodium retention in the target tumor tissue will be descriptively summarized with mean 
± standard deviations. We will correlate immune biomarkers and tumor response measures using 
the Spearman correlation of ±0.63 or larger differences from 0, at 0.80 power and alpha=0.05 (two-
sided).
12.1.6 Phase II Sample Size Justification (Cohort A and  Cohort B)
Let π equal the proportion of CR+PR responses. The primary analysis, for Cohort A and  Cohort 
B , will consist of a one-sided exact binomial test of H0: π=0.05 versus Ha: π>0.05 at level α=0.05.  
Given n=18 subjects and setting power at 0.80 we will be able to detect an alternative response 
rate of π>0.29.  The primary analysis for Cohort B will consist of a one-sided exact binomial test 
of H0: π=0.30 versus Ha: π>0.30 at level α=0.05.  Given n=39 subjects (including n=6 from the 
Phase I) and setting power at 0.80 we will be able to detect an alternative response rate of π>0.50. 
A secondary analysis of efficacy will utilize an ordinal regression of response (CR, PR, SD, PD) 
as a function of baseline tumor volume. All key secondary outcomes will be considered suitably 
continuous will be analyzed with an analysis-of-covariance (ANCOVA) approach regressing 
change from baseline to three months on the baseline value of the respective measure adjusted for 
baseline tumor volume, age, and sex. The null hypothesis of interest is H0: β0=0,β1=0 versus Ha: 
β0≠0,β1≠0, where β0 is the ANCOVA intercept and β1 is the regression slope, respectively. All 
tests will be at level α=0.05. Since both the FACT-L based measures and the 6-minute walk 
measures are likely to be highly cross correlated no adjustments for multiple testing will be 
considered a priori. For Cohort A and Cohort B , each continuous endpoint and given n=18 subjects 
we will have 0.80 power to reject the joint null hypothesis if the slope and intercept account for 
39% of the overall variation or larger in the given endpoint. For Cohort B, each continuous 
endpoint and given n=39 subjects we will have 0.80 power to reject the joint null hypothesis if the 
slope and intercept account for 20% of the overall variation or larger in the given endpoint.
12.1.7 Interim Analysis and Criteria for Early Termination of the Study
A futility analysis of efficacy will be carried out for Cohort B after n=20 subjects have completed 
the trial.  A conditional power calculation will inform the decision to continue accrual.
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12.1.8 Safety Monitoring (Cohort A and Cohort B)
Safety and tolerability will be assessed by incidence, severity, and changes from baseline of all 
relevant parameters including adverse events (AEs), laboratory values and vital signs.
Vital sign results (systolic and diastolic blood pressure, pulse, respiration, and temperature) will 
be summarized descriptively for each scheduled and unscheduled protocol time point. Changes 
will be calculated relative to the assessments at baseline.
The changes in hematology, chemistry, and other laboratory values will be summarized 
descriptively for each scheduled and unscheduled protocol assessment time point. Changes will be 
calculated relative to the values collected at baseline. Data listings of all laboratory data collected 
during the study will be presented. Laboratory values outside normal limits will be identified in 
data listings and will include flags for high and low values.
The frequency of toxicities will be tabulated by grade. All participants who receive any study 
treatment will be considered evaluable for toxicity.
12.1.9 Safety Monitoring Lead-In (Cohort B)
The safety profile will be measured by recording treatment related AEs that are ≥ grade 4 with 
attribution of ‘possible’, ‘probable’, or ‘definite’, according to the NCI CTCAE v5.0. The safety 
measures will be evaluated in all patients who received image-guided I-PDT preceded by standard 
of care p-XRT of 8 Gy x1 for the treating their MCAO. The following decision rules will be 
followed: (i) If 0/3 AE≥ grade 4’s are observed it will be concluded the therapy is safe. (ii) If 1/3 
AE≥ grade 4’s are observed, enroll 3 more patients for safety evaluation. If 1/6 AE≥ grade 4's are 
observed, it will be concluded the therapy is safe.  If ≥2/3 or ≥2/6 AE≥ grade 4’s are observed it 
will be concluded that therapy is unsafe. We calculated via Monte Carlo simulation that if the AE≥ 
grade 4 rate is 20%, 30% and 40% the respective probabilities of declaring the treatment unsafe 
are 0.26, 0.51 and 0.70.
13 ETHICAL AND REGULATORY STANDARDS
13.1.1 Ethical Principles
Roswell Park will be the IRB of record for this multi-site study.  Accruals will occur at Roswell 
Park Cancer Institute and accompanying external sites.  Any participating site will enter into a 
reliance agreement with the Roswell Park IRB and proper IRB approval of each site will be given 
prior to participation in the study.
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
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study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
13.1.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant in accordance with GCP guidelines using the approved informed consent form, before 
any study specific procedures (including screening procedures) are performed. The informed 
consent form acknowledges all information that must be given to the participant according to 
applicable GCP guidelines, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The participant should also be made aware that by signing the 
consent form, processing of sensitive clinical trial data and transfer to other countries for further 
processing is allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant research file. At any stage, the participant may withdraw from the study and 
such a decision will not affect any further treatment options.
14 STUDY RESPONSIBILITIES
14.1.1 Data Collection
Cohorts A and B patient-reported outcomes from questionnaires will be stored using the secure 
Roswell Park REDCap database, while the CTMS will be used to collect physician-assessed 
clinical outcomes.
Patient survey data will be kept on the secure Roswell Park REDCap database, and will be 
accessible only by the PI, Co-Investigator, and the CRS representative. Patient clinical data will 
be kept in CRS CTMS. The REDCap database will be password protected. All records will be kept 
in a limited access environment. All computer entry and networking programs will be done using 
PIDs only.
Full build studies are managed by Roswell Park CRS Data Management for analysis by Roswell 
Park Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities will be performed using eClinical. eClinical is a suite of software tools 
that enables the collection, cleaning and viewing of clinical trial data. CRS data management will 
design the study-specific database and facilitate its development by the eClinical Information 
Technology team. Once the database design is approved by the Investigator, Statistician, and 
Clinical Research Coordinator, the database will be put into production and data entry can begin. 
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Data can be entered and changed only by those with the rights to do so into the eCRFs.
14.1.2 Maintenance of Study Documents
Essential documents will be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park.
15 ADMINISTRATIVE RULES
15.1.1 Revisions to the Protocol
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation.
15.1.2 Termination of the Study
It is agreed that, for reasonable cause, either the Roswell Park Investigators or the Sponsor, may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, Roswell Park may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of participants enrolled in 
the study.
15.1.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
Completed Cohort A and B participant questionnaire data will be entered into a secure REDCap 
Database on the Roswell Park server via tablet by the patient, or the usage of paper questionnaires 
when tablets are unavailable (paper questionnaire information will then be entered by the study 
Clinical Research Coordinator). This will be accessible only to investigators on the study. For 
analysis, data will be entered into OnCore which will only be accessible to authorized individuals. 
Any paper files containing identifiers will not be taken off Roswell Park premises. PHI will not be 
reused or disclosed to any other person or entity.
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16 APPENDICES
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Appendix A
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix B
Patient Instructions
Patient Instructions for Photofrin® and Laser Treatment
You should protect yourself from daylight while in the hospital and when you go home. The 
major danger is severe sunburn of the skin. Photofrin® stays in your body for a long time after 
you have received treatment. Therefore, you must be careful and limit your exposure to daylight. 
You are most likely to be burned by daylight for 6 to 8 weeks after receiving the drug. However, 
you should limit your daylight exposure for about 2 months after the treatment. Several 
suggestions are listed below:
1.
For the first 1 month keep the drapes closed (drawn) so that daylight does 
not enter your room(s) in the hospital and when you go home. You must 
remember that there is a danger from direct sunlight even on days that are 
overcast and cloudy.
2.
Your eyes are also sensitive to direct daylight, so you should wear dark 
sunglasses (100% UV protection) for at least 2 months after receiving 
Photofrin®.
3.
If you must be exposed to daylight, you should wear a hat with a large brim, 
sunglasses, gloves to protect your hands, a long-sleeved shirt or blouse, 
slacks, socks, and a scarf to protect your neckline.
4.
Poor circulation in any area of your body may result in that area retaining 
the Photofrin® for a longer period of time than the rest of your body, 
and this area will need extra protection for a longer time than 2 months.
5.
You may be exposed to indoor light from a low wattage (60 watt) light bulb 
for up to ten hours each day. For longer periods of exposure to light, dimly 
lit rooms are advisable (60 watt). Exposure to Fluorescent lighting is OK. 
You may watch TV and use indirect lights such as the lights in the 
hospital found above your bed, which shine toward the ceiling. Try not 
to use Ultra-violet or Halogen lights.
o
For reading, it would be useful to use a small book lamp (example: Itty-bitty 
Book lamp). The book light will prevent you from having the light shine on you.
6.
Do not have your eyes examined for at least 2 months after receiving 
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Photofrin®. This is a precaution to prevent any retina damage that could 
occur from exposure to the bright exam light used in eye exams.
7.
Please also do not go to the dentist in the 2-month period after receiving 
Photofrin® to prevent any oral/facial skin burning from the bright exam 
light.
8.
Showers and baths are allowed.
9.
You must report any redness, swelling, tenderness, blistering, sunburn, or any 
other event that does not usually happen to you.
10.
Remember that your doctor is here to study the usefulness of Photofrin® 
and photodynamic therapy for the treatment of tumors; your questions, 
concerns, and symptoms are important.
11.
Please help the doctor to learn more about you and your treatment by 
keeping lists of questions, concerns, and symptoms. Your doctor will 
address these when you see them. Also, remember that the nurse can aid 
you at any time.
12.
You are welcome to bring any family member or close friend to your 
appointments to help you in communicating with your doctor.
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Skin Testing After Photofrin®
1. When should I test my skin?
Approximately 1 month after receiving the drug Photofrin®.
2. What do I do?
Cut a hole in a paper bag approximately 2-inch diameter. Place the 
bag over your forearm. Cover all other skin thoroughly. Expose the 2-
inch diameter of the forearm skin to direct sunlight for one minute, 
then examine for evidence of skin reaction, such as redness, blistering 
or burning sensation. If there is no reaction, expose the skin again, 
and check it in another minute. Repeat this procedure up to eight more 
times, provided there is no sign of skin reaction.
3. What if I see a skin reaction?
Immediately cover the exposed skin and stop the skin test. You may retry 
skin testing in a few days. Contact your doctor or nurse to find out more 
information.
4. What if I don’t have a skin reaction?
If there is no reaction after the above procedure, cover the exposed skin 
and protect yourself from sunlight for 24 hours. Re-examine the exposed 
skin at the end of this time. If there is no delayed skin reaction, slowly 
begin to increase your time in direct light.
5. Should I use sunscreen?
No. A sunscreen will not help protect your skin from the sun when using Photofrin®.
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Appendix C Instructions for Multi-Site Studies – can enroll patients into Cohorts A and B 
only
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Comprehensive Cancer Center
CRS Quality Assurance (QA) Office
CRS-QA@RoswellPark.org 
Elm and Carlton Streets
Buffalo, New York 14263
Telephone:
Monday - Friday; 8:00 AM to 4:30 PM EST
716-845-8084
After hours, weekends, and holidays request the Roswell Park Investigator
716-845-2300
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any 
participants wishing to participate, prior to any procedures or treatment.

An informed consent template is provided by Roswell Park and can be amended to 
reflect institutional requirements.

All consent changes must be reviewed by Roswell Park CRS QA Office prior to 
submission to the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being 
used.

Within 5 business days, notify the Roswell Park CRS QA Office of all participant 
withdrawals or consent to limited study participation and appropriately document the 
discontinuation and the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
Roswell Park does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be emailed (CRS-QA@RoswellPark.org) to the 
Roswell Park CRS QA Office within 1 business day of the date the participant is consented. Once 
the Investigator has determined that eligibility has been met, complete the eligibility check list and 
email it to the Roswell Park CRS QA Coordinator at CRS-QA@RoswellPark.org.
Protocol Randomization Instructions
Patients at Roswell Park Cancer Institute will be registered directly by Roswell staff using the 
web-based registration system. For patients at institutions outside Roswell Park Cancer Institute, 
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the local site staff will contact the appropriate coordinator to register the patient using the web-
based registration application as developed by the GOG Foundation Statistical & Data 
Management Center in conjunction with the study biostatistician. Within 24 hours the QA 
Coordinator will email the randomization arm assignment and participant ID # back to the site PI. 
The site PI will send a confirmation email back to the QA Coordinator verifying the randomization 
arm for the specified network participant. Questions regarding randomization issues can be 
emailed to alan.hutson@roswellpark.org.
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the Roswell Park 
CRS QA department, site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principal Investigator.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.

If an entry has been documented in error put a single line through the entry and initial 
and date the change. The Roswell Park CRS QA Coordinator must be able to read what 
has been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of Roswell Park to inform the Investigator/ institution as to when 
these documents no longer need to be retained. If, for any reason, the Investigator 
desires to no longer maintain the study records, they may be transferred to another 
institution, another investigator, or to Roswell Park upon written agreement between 
the Investigator and Roswell Park.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug 
received, dispensed to participants and wasted, lot number, date dispensed, participant 
ID number and initials, quantity returned, balance remaining, manufacturer, expiration 
date, and the initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific; they are study source 
documents and will be used to verify compliance with the study.
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
An inventory count must be performed with each transaction. Any discrepancies shall 
be documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have 
its own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park CRS QA Coordinator within 1 business day of 
being made aware of the SAE. A preliminary written report must follow within 1 business day of 
the first notification using the following forms:

Roswell Park Oncore SAE form

Notify Pinnacle Biologics Inc. (Contact: Sherry Swint, swints@pinnaclebiologics.com)
Name, address, phone, e-mail
The principal investigator or designee will inform Roswell (via email using both the Oncore SAE 
form and MEDWATCH 3500A form) within twenty-four (24) hours of first awareness of any 
event that meets the above criteria. Both forms should include all available information, including 
a brief narrative describing the SAE, attributions, and any other relevant information. Upload all 
related (redacted) source information into OnCore along with the completed forms signed by the 
PI. 
Forms 
will 
be 
submitted 
to 
the 
CRS 
QA 
Office 
via 
email 
to 
SafetyEventReporting@RoswellPark.org. 
A complete follow-up report must be sent to the Roswell Park CRS QA Coordinator when new 
information becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 17.7.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park CRS QA Coordinator within 1 business day of being made 
aware of the Unanticipated Problem by completing the Roswell Park Unanticipated Problem 
Report Form and emailing it to the Roswell Park CRS QA Coordinator to 
SafetyEventReporting@roswellpark.org.
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Appendix D FACT-L Quality of Life Questionnaires
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