Calypso-based Deep Inspiration Breath Hold (DIBH) Radiation Treatments of Lung Cancer
Phase: NA
Conditions: Non-small Cell Lung Cancer (NSCLC)
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
 
MSK Protocol Cover Sheet 
 
Calypso-based Deep Inspiration Breath Hold (DIBH) Radiation Treatments of Lung 
Cancer 
Principal Investigator: Daphna Gelblum, MD in the Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
1 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
2 
Amended: 03-JUN-2016 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 6 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................... 10 
4.1 
Design .......................................................................................................................... 10 
4.2 
Intervention ................................................................................................................... 11 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 11 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 13 
6.1 
Subject Inclusion Criteria .............................................................................................. 13 
6.2 
Subject Exclusion Criteria ............................................................................................. 13 
7.0 
RECRUITMENT PLAN ..................................................................................................... 14 
8.0 
PRETREATMENTEVALUATION ..................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 15 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 20 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 21 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 21 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 23 
14.0 BIOSTATISTICS .............................................................................................................. 23 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES25 
15.1 Research Participant Registration ................................................................................. 25 
15.2 Randomization .............................................................................................................. 25 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 25 
16.1 Quality Assurance ......................................................................................................... 25 
16.2 Data and Safety Monitoring ........................................................................................... 25 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 26 
17.1 Privacy.......................................................................................................................... 27 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 27 
17.2.1 
 28 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 28 
19.0 REFERENCES ................................................................................................................. 29 
20.0 APPENDICES .................................................................................................................. 32 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
3 
Amended: 03-JUN-2016 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This trial will investigate the feasibility of implanted anchored Beacon® electromagnetic lung 
transponders (Calypso®) to guide and monitor deep-inspiration breathhold (0IBH) treatments 
in patients with inoperable thoracic malignancies. Currently, many patients with thoracic 
tumors cannot be treated to the optimal intended radiation dose due to strict dosimetric 
limitations for normal tissues nearby. Furthermore, all lung tumors that are treated to the full 
radiation dose exhibit tumor motion with respiration which requires the radiation field to be 
expanded to an internal target volume (ITV) that encompasses all possible tumor positions 
during the treatment in order to avoid missing the target. This results in the unnecessary 
treatment of larger amounts of normal lungs, esophagus and other nearby organs at risk 
which are responsible for the majority of adverse events in thoracic radiation oncology. 
 
Several techniques to reduce respiratory motion during radiation therapy have been explored 
and are clinically available. One of the most promising approaches is to immobilize the tumor 
by having patients hold their breath. This has been found to result in effective reduction of 
tumor motion as well as an expansion of the lungs and other normal tissues to be moved 
away from the radiation target. However, 0IBH is currently performed based on external 
markers and radiographic surrogates such as the diaphragm to monitor the patient's 
breathhold. It is known that external markers and the diaphragm frequently do not correlate 
well with internal motion and tumor position. Using implanted Calypso beacons would for the 
first time allow real-time monitoring of tumor position and breathhold in patients with thoracic 
malignancies. This technology was initially developed for prostate cancer patients with great 
success. A new anchored lung transponder has been developed for its application in thoracic 
malignancies in which there is significantly more tumor motion. Based on our experience in 
prostate cancer patients, it is our expectation that this transponder would improve the 
reproducibility of localizing and monitoring tumor position during breathhold in real time, 
decrease radiation dose to organs at risk in close proximity to the radiation target and allow 
dose escalation to desired radiation doses. In addition, limiting tumor motion to a minimum 
and thus increasing our confidence in intrafraction tumor position would allow decreasing the 
ITV margins that are currently added to the tumor to account for tumor motion. This would 
ultimately lead to improved local control rates and decreased adverse events attributable to 
the radiation treatments. 
Patients who are able to hold their breath at least for 5 breathholds of more than 20 seconds 
each and are planned to undergo radiation treatment to tumors in the thorax will be eligible 
for this study. 
First, 2-3 anchored lung transponders will be placed bronchoscopically in or near the target 
tumor. Patients will be given instructions to learn and practice the 0IBH maneuver. After a 
minimum of 3 days, the patient will undergo a CT simulation for radiation treatment planning, 
and a free-breathing 40 CT scan and a CT scan in 0IBH will be obtained using the Varian® 
Real-time Position Management™ (RPM) system. Two radiation therapy plans will be 
developed, one based on the free-breathing 40 CT scan and one based on the 0IBH scan. At 
the time of treatment, the patient will be initially positioned according to standard setup 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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Amended: 03-JUN-2016 
 
 
procedures based on external tattoos and room lasers. A free- breathing trace of the Calypso 
transponders will be obtained to allow the patient to settle on the treatment table and to study 
real-time respiratory traces. The patient will then be asked to perform a therapist-coached 
modified slow vital capacity maneuver and DIBH maneuver [1] and hold their breath. Patients 
will have the ability to perform this maneuver with or without biofeedback from digital goggles 
that are placed over the patient's eyes and display the breathing trace of the Calypso 
transponders. The use of the digital goggles will be determined by patient preference or at the 
discretion of the treatment team. This will allow us to investigate whether real-time biofeedback 
adds to the reproducibility of patients holding their breath. A DIBH cone-beam CT will be 
acquired in approximately three breath-holds, once a week for standard fractionated RT 
patients or with each fraction for SBRT patients. After review and approval of the images, the 
patient will be treated while holding their breath using the DIBH maneuver. In standard 
fractionated RT patients the radiation treatment will be guided by the external tattoos and 
daily 2D kV imaging. The Calypso transponder signal will be used to monitor the level of the 
breath-hold during treatment. The breath-hold level based on the Calypso transponder signal 
will be verified daily by the 2D imaging and once a week in 3D by the DIBH cone-beam CT. 
In SBRT patients, the radiation treatment will be guided by the external tattoos and daily 
DIBH cone-beam CT. The Calypso transponder signal will be used to monitor the level of the 
breath-hold during treatment. The therapists will monitor the respiratory trace signal from the 
Calypso transponders throughout the treatment and will initiate the radiation treatment 
delivery when the patient holds his/her breath within the tolerance level the patient has been 
assigned to. This will be continued up until the initially planned 30 patients are accrued.. Should 
the transponder signal indicate that the target has moved outside of the preset tolerance, the 
therapists will hold further radiation treatment delivery until the patient's breathhold has 
returned to the desired target range or until the patient's setup has been corrected. In the 
additional 25 patients planned, the margins will be reduced in a step-wise fashion. The gate will be 
decreased 1mm per each set of 5 patients until the duty cycle (beam-on time) and number of DIBH 
attempts are doubled. The gate at which this occurs will be considered the minimum clinically 
feasible gate 
The study will determine for the first time based on real-time tumor positioning information 
whether patients are able to reproducibly hold their breath in DIBH within excursions of 5.+/- 
0.5cm or less. Furthermore, it will determine whether visual biofeedback improves the 
reproducibility of the breathhold. It will provide a unique dataset that will allow us to 
determine the concordance level of real-time tumor position information from the Calypso 
transponders, external surface signal and radiographic imaging. Ultimately, this study will 
allow us to quantify the decrease in radiation dose to organs at risk, decreased toxicity and 
amount of dose escalation made possible by the DIBH maneuver using real-time tumor 
position information. 
Patients will be considered evaluable for protocol when they have had successful calypso 
beacon implantation without the beacons migrating> 5cm, and they have completed training 
in DIBH. In the extension of the protocol described below, 25 patients will be accrued; the 
expected time for completion of this study is 3 year from its approval. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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Amended: 03-JUN-2016 
 
 
 
Radiation 
Treatment setup 
Calypso signal 
recording 
 RT treatment with DISH 
with or without visual 
biofeedback 
 
Follow-up 
 
months after RT 
with clinical 
assessments 
and diagnostic 
CT chest 
 
 
 
Bronchoscopic 
Calypso 
Beacon 
Implantation 
Simulation 
 
Free-breathing 
---+ 
scan 
4D CT scan 
- DISH CT scan 
Clinical 
evaluation for 
5x 20 second 
breathhold 
---+ 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objectives: 
• 
To evaluate the feasibility of using internal tumor surrogates (Calypso beacons) during 
repeated deep inspiration breath hold maneuvers for DIBH radiation treatments. 
Secondary objectives: 
• 
To compare the reproducibility with visual versus without visual biofeedback. 
• To assess differences in the ability of maintaining the DIBH maneuver within the gate with and 
without visual biofeedback 
• 
To measure the residual intrafraction tumor motion and associated improvement in normal 
tissue dosimetry during DIBH based on the Calypso lung transponder signal as a surrogate 
• 
To measure the increase in dose escalation and the potential for decreasing margins made 
possible by Calypso-guided DIBH 
• 
To determine the minimum clinically feasible gate margin for radiation 
• 
To assess tumor shrinkage, beacon position and centroid changes in conventionally 
fractionated patients 
• 
To assess intra- and inter-fraction variation in lung volume preservation of multiple DIBH 
maneuvers 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 Respiratory motion in lung cancer radiation treatment 
Non-small cell lung cancer (NSCLC) remains the malignancy associated with the highest 
number of cancer-related deaths in the US. 
Patients with inoperable early-stage NSCLC are typically treated with high-dose stereotactic 
body radiation therapy (SBRT) resulting in excellent local control of >90%.[2-5] SBRT is now 
also being used for metastatic disease in the lungs, with equally good local control rates and 
low rates of toxicity as observed in early-stage NSCLC.[8-11] Currently, a 4D free breathing 
CT scan is obtained at simulation. The 4D scan is used to determine the entire volume swept 
out as the tumor moves through the respiratory cycle. This volume (the ITV) is further 
increased by the addition of 0.5 to 1 cm margins of healthy tissue to create the volume (the 
target) which is treated to the prescription dose. The margins of healthy lung are needed to 
account for positioning uncertainties during treatment. Significant respiratory tumor motion 
results in an increase of the ITV and therefore the volume of healthy lung within the target 
volume. The volume of healthy lung within the target, and the volumes of adjacent normal 
tissues such as chest wall increase rapidly with increasing ITV size. Since these patients are 
usually medically inoperable due to severe emphysema or other medical comorbidities, any 
reduction in radiation dose to organs at risk is desirable. The most common toxicities observed 
with SBRT include respiratory toxicity, esophagitis, chest wall pain, and rib fractures. The rate 
of toxicities from SBRT appears to be directly related to the irradiated volume, the tumor 

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location and the radiation dose.[5-7] 
 
Locally-advanced NSCLC patients receive fractionated RT, ideally 60 Gy in 30 fractions when 
given with concurrent chemotherapy.[12-14] Frequently, the predicted toxicity from radiation 
dose to the lungs and spinal cord using widely agreed upon dose constraints to these organs 
limit our ability to treat patients to the optimal prescription dose. [15, 16] Respiratory motion 
can significantly increase the treated volume, especially in patients with already large tumors. 
The most common toxicities in this patient population are esophagitis and respiratory toxicity 
including radiation pneumonitis.[14, 17] The same challenges exist for patients with limited­ 
stage small cell lung cancer treated with chemotherapy and thoracic radiation therapy.[18-20] 
Techniques to address intrafraction tumor motion include abdominal compression, respiratory 
gating, and active breathing control (ABC).[21] While these are all clinically approved 
techniques, they are not currently widely used in practice. Abdominal compression can be 
uncomfortable to the patients and does not necessarily control internal motion well.[22] In 
addition, it compresses the lungs and does not consistently improve sparing of normal tissues, 
but may actually worsen the dosimetry.[23] Respiratory gating based on external markers can 
be misleading due to the potential discrepancy between external marker and true internal 
target motion.[24, 25] ABC is an involved process using a spirometer which is frequently 
uncomfortable to the patient, and there are problems with changes in tidal volume, volume 
expansion, patients' response and adaptation to the system.[26, 27] These techniques all 
depend on unreliable surrogates of the target position, and frequently cannot be tolerated by 
patients because of patient discomfort or are too complex for patients to manage, making 
them far from ideal . 
In principle, DISH is a promising approach to minimize respiratory motion. It has been shown 
to reduce respiratory motion, increase lung volume, and allow dose escalation.[1, 21, 28, 29] 
Currently, DISH is feasible in about 25% of patients who undergo lung radiation therapy. This 
is because of the difficulty many patients have in adequately performing the modified slow vital 
capacity maneuver currently used for DISH, which consists of a deep inhalation, deep 
exhalation, second deep inhalation and breath hold. When performed well, the maneuver 
results in a reproducible lung inflation and thereby tumor position. We currently use it in 
selected patients who are able to perform this maneuver well. Currently, DISH is based on 
external markers e.g. RPM, or radiographic surrogates such as the diaphragm, since lung 
tumors are typically not well enough delineated on 2D radiographs. However, DISH based on 
surrogates like external markers and radiographic surrogates such as the diaphragm is 
fraught with the same problems as respiratory gating based on external markers or the ABC 
device. There may be a lack of correlation between external marker and internal target 
motion, e.g. drifts or shifts of the internal target that may not be accurately detected by an 
external marker.[24, 25] 
We therefore propose using implanted Calypso lung transponders for guidance and 
monitoring of DISH in patients with thoracic malignancies who are treated with radiation 
therapy. This would represent a significant improvement over current DISH techniques 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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by having available reliable, real-time tumor position information prior to and throughout 
the radiation treatment delivery. With real-time tumor position feedback, it will not be 
necessary to perform the difficult DIBH maneuver; instead, a simple inhalation and 
breath hold will be sufficient to position the tumor with high reproducibility. We expect 
this to substantially improve the patient eligibility rate compared to other methods for 
DIBH guidance, such as spirometry or external markers. As a result, we expect to more 
frequently be able to treat patients with locally-advanced lung cancers to the intended 
total dose of 60 Gy as a direct benefit to patients from using this technique. If successful 
this study will lead to a new clinical technique that will allow us to decrease the volume 
of healthy lung and adjacent tissues exposed to high doses, thus further decreasing the 
risk for toxicities. This makes possible a strategy for dose escalation and thus the 
potential for improved local control in patients where current treatments are limited by 
normal tissue constraints. 
 
3.1.1 Rationale for the use of Calypso lung transponders 
 
In prostate cancer RT, the use of electromagnetic Calypso transponders has been found to 
allow real-time tracking of inter- and intrafraction motion, as well as reduction in PTV margins 
and patient-reported acute morbidity.[31-33] Submillimeter accuracy was established to a 
range of 27cm distance from the detection array and at speeds of up to 3cm/s, thus making it 
the most accurate real-time motion monitoring device available.[34] Electromagnetic Calypso 
transponders revealed prostate motion of >5mm in 97% of patients, thus providing a 
significant benefit over conventional patient positioning. In addition, a cost-utility analysis 
demonstrated significant benefits in quality-adjusted life years (QALY) compared to 
conventional localization.[35] Outside of prostate cancer, these transponders have been 
shown to also be feasible for inter-and intrafraction motion detection in pancreatic cancer.[36] 
The implantation of the transponders as part of the staging laparoscopy was well-tolerated and 
minimal migration of the transponders was observed. It was shown that breathholding 
significantly decreased tumor motion. 
Until recently, no such transponder system was available for lung tumors, due to the difficulty 
of developing a transponder that would stay fixed after implantation. Varian Medical has now 
developed a modified transponder for use in lung cancer by adding anchors to the same 
transponders that are in routine clinical use for prostate cancer. The anchors of the lung 
transponder stabilize the transponder in small airways of the lungs. A pilot study from the 
University of Stellenbosch, Tygerberg, South Africa, and the University Hospital Basel, Basel, 
Switzerland, has found the first use in humans to be safe and feasible.[22, 37] No patients 
developed pneumonia, pneumothorax or adverse pulmonary symptoms. Significant 
intrafraction variability of tumor motion was detected, even with the use of external 
compression devices. Currently, these anchored transponders are being tested for safety and 
feasibility in the lungs in an ongoing larger clinical study ("Evaluating an Anchored 
Transponder in Lung Cancer Patients Receiving Radiation Therapy" (NCT01396551 ), 
www.clinicaltrials.gov). Preliminary findings of this study in the US showed that out of 48 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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evaluable patients, two patients experienced a pneumothorax (Grade 2), one patient had 
anesthesia-related cardiac arrest (Grade 4), two patients experienced cough (Grade 2) and 
one patient had dyspnea (Grade 2) after the bronchoscopy, one patient had lung infection 
(Grade 3), and two patients had migration of one fiducial marker each that did not impact the 
ability to track the tumor during radiation treatments.[38, 51.] The use of Calypso transponders 
holds the potential for a great benefit of real-time tumor position information without the use of 
ionizing radiation from additional intrafraction imaging. Calypso transponders have been 
routinely used in our department as a motion monitoring system for prostate RT for about 5 
years. The entire system including 4D console, electromagnetic array, tracking station and 
optical system is in place on a linear accelerator that is equipped for lung RT and on-board kV 
imaging. 
 
3.1.2 Rationale for the use of SuperDimension® system and radial probe 
Endobronchial Ultrasound 
The SuperDimension® system is an electromagnetic navigation bronchoscopy (ENB) system 
that allows minimally invasive procedures in the periphery of the lungs with higher accuracy 
than conventional bronchoscopy alone[39]. It allows bronchoscopic biopsies, fine needle 
aspirations and fiducial marker placements with a reduced risk of pneumothorax as compared 
to transthoracic approaches. Given its extended range it has been shown to reach peripheral 
lung tumors with accuracy >80%. This system allows for virtual guidance based upon CT 
reconstructions and electromagnetic tracking. Therefore, real-time confirmation can be 
provided by radial probe endobronchial ultrasound (rEBUS; Olympus Medical) which further 
improves the accuracy.[40, 41] In certain cases, rEBUS alone is sufficient to localize 
peripheral pulmonary lesions.[42-45] However, it has been shown that the combination of 
these technologies provides the highest diagnostic yield for biopsies of peripheral lung lesions 
by improving lesion localization accuracy. Both of these localization technologies are in 
routine use by our interventional pulmonologists and thoracic surgeons and are fully 
compatible with the Calypso anchored transponder system. 
Prior studies have demonstrated safety in placing other fiducial markers bronchoscopically 
(ENB +/- rEBUS) for lung tumors with low migration rates and low pneumothorax rates.[46- 
48] Comparisons of transcutaneous versus ENS-guided fiducial marker placement shows a 
higher risk of pneumothorax in the transcutaneous group.[48] Furthermore, early studies in 
Switzerland and South Africa have shown the feasibility, stability and safety of bronchoscopic 
Calypso transponder placement.[37] We therefore propose to use the SuperDimension ENB 
system and rEBUS for the placement of Calypso transponders whenever possible. 
Alternatively, conventional bronchoscopy may be used for Calypso transponder placement 
where feasible. Radial probe endobronchial ultrasound (EBUS) may be used when needed 
for more accurate placement of the Calypso transponders. 

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IRB Number: 13-174 A(15) 
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3.2 Preliminary Data 
 
DIBH has been previously explored using coached breath-hold monitored by spirometry [28, 
49] and radiographic imaging and using spirometry plus the Elekta "ABC device" together 
with radiographic imaging[21 ][18, 27]. An initial series of 5 patients at MSKCC who 
underwent CT scans under 4 different respiration conditions including DIBH showed that 
DIBH can reduce the volume of lung receiving more than 25 Gy by 30% compared to free­ 
breathing radiation plans. Patients were able to comfortably hold their breath for 12 -16 
seconds and perform 10-13 breath-holds in a single session.[28] 
We then showed that coached DIBH with spirometer monitoring decreased estimated normal 
tissue complication probabilities while allowing for increased tumor doses.[1] Patients were 
initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, 
a second deep inspiration, and breath-hold in deep inspiration (DIBH). Simulation, 
verification and radiation treatments took place during this last phase of DIBH. Seven 
patients received a total of 164 treatment sessions with excellent tolerability. None of the 
seven patients needed to discontinue treatment or resume the free-breathing backup method 
due to fatigue or inability to perform the DIBH maneuver. On average, the radiation dose could 
be increased from 69.4 Gy to 87.9 Gy without increasing the risk of toxicity by using DIBH. 
In a subsequent analysis of 7 patients undergoing over 250 treatments, we found that 
reproducibility was excellent as judged by spirometry and verification films using the 
diaphragm as a surrogate. Presumed respiration-dependent tumor motion was thus 
significantly reduced from 0.8 +/- 0.5cm to 0.02 +/- 0.14 cm (mean and standard deviation) 
compared to free breathing.[49] The main advantages observed with the use of DIBH were an 
increase in lung volume and motion of the PTV away from critical structures, e.g. spine. Thus, 
DIBH is an excellent tool to decrease target motion, decrease radiation dose to normal organs 
at risk and thus allow dose escalation to the tumor. DIBH treatments are currently clinically 
used in our department in appropriate patients. However, all DIBH treatments to date have 
relied on external or indirect markers as surrogates, sometimes combined with fluoroscopy or 
radiographic imaging for position verification. Given the potential pitfalls of external 
surrogates, we propose to investigate and improve DIBH treatment delivery using real-time 
tumor position information from implanted electromagnetic Calypso anchored transponders. 
In addition, the use of Calypso anchored transponders would simplify the DIBH maneuver to 
a single, comfortable breathhold, thus making it an attractive treatment option for a wider 
patient population. 
Early studies in Switzerland and South Africa have shown the feasibility, stability and safety of 
bronchoscopic Calypso anchored transponder placement.[37] They have also demonstrated 
successful intrafraction motion detection.[22] An ongoing prospective international trial 
explores the safety and feasibility of endobronchial implantation of these electromagnetic 
fiducials. Interim results reported at ASTRO 2012 showed that 149 transponders were 
successfully implanted in 48 patients.[38, 51.] Two patients developed cough (G2), 1 patient 

Memorial Sloan Kettering Cancer Center 
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had dyspnea (G2) after bronchoscopy, two patients had pneumothoraces (G2), one patient 
had an anesthesia-related cardiac arrest (G4), and one patient had a lung infection (G3) 
concurrent with marker migration. One other patient experienced an asymptomatic migration 
of one transponder in a large airway that did not prevent localization and tracking by the 
Calypso system. Positional stability of these transponders is therefore 99% to date. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
 
The primary objective of this study is to evaluate the feasibility of Calypso transponders as 
an internal tumor surrogate to guide DIBH radiation treatments in real time. 
 
The use of Calypso transponders has the potential to result in improved reproducibility of 
tumor positioning during DIBH treatments. We therefore plan to analyze the obtained 
respiratory traces from the Calypso signal as well as the imaging data from CBCTs and 
radiographs to explore a set of secondary objectives. These include a comparison of the 
reproducibility of DIBH tumor position with visual versus without visual biofeedback (for 
patients who agree to use the digital goggles), measurement of any residual intrafraction 
tumor motion, improvement in normal tissue dosimetry during DIBH based on the Calypso 
lung transponder signal as a surrogate, and determination of any increase in dose 
escalation and the potential for decreasing margins made possible by Calypso-guided 
DIBH. Given the successful radiation localization in the first 25 patients, we will also aim 
to determine the minimum clinically feasible gate margin for radiation. We will reduce the 
gate from +/-5mm by 1mm for every 5 patients treated. Once the minimum gate is 
determined, the remaining patients will be treated at +1mm from this value. We will also 
plan to enroll at least 10 additional conventionally fractionated patients to assess the 
impact of tumor shrinkage on beacon position and centroid changes. Finally, lung volume 
preservation will be assessed on wide field of view cone-beam CTs and compared intra­ 
and interfraction within each patient to check for reproducibility or variability of lung 
volumes across multiple DIBH maneuvers. 
 
The radiation treatment for patients on this study will be performed according to routine 
procedures using standard equipment, techniques and treatment planning procedures. The 
radiation dose prescription criteria will not be changed based on the DIBH maneuver or 
Calypso transponder implantation on this study. Patients will be followed as per our 
institutional standard at approximately 3, 6, 9 and 12 months after radiation treatments. 
Following completion of study participation, patients will be followed as per our institutional 
standard. They will be evaluated for any potentially transponder-related toxicity. Any 
toxicities will be carefully evaluated case by case according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v4.0. 

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4.2 
Intervention 
 
The Calypso signal will be used to verify and monitor the patient's DIBH maneuver at each 
treatment session. In addition, physician evaluation of patient setup accuracy will be 
performed using all available images and adjustments will be made as per standard practice. 
Should the transponder signal indicate that the target has moved outside of the preset 
tolerance, the system will automatically hold further radiation treatment delivery until the 
patient's breathhold has returned to the desired target range or until the patient's setup has 
been corrected. 
For imaging, we will use the on-board kV imaging system. Patients undergoing SBRT will 
receive standard CBCTs for patient setup, but no more than 2 CBCTs per treatment for 
protocol purposes. Patients undergoing conventionally fractionated RT will undergo weekly 
imaging sessions with CBCT for protocol purposes. A maximum of 8 CBCTs over the entire 
treatment course will be permissible for protocol purposes in patients undergoing 
conventionally fractionated RT. 
Radiation therapy dose guidelines, treatment planning process and followup will not be 
changed by enrollment on this study. 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
The major components required for this study are the anchored Calypso beacon 
transponders, the SuperDimension electromagnetic navigation bronchoscopy system, 
Olympus radial probe endobronchial ultrasound and RPM system on the simulator and the 
Calypso tracking system at the treatment machine. 
The anchored Calypso beacon transponders and training and user documentation will be 
provided by Varian Medical Systems, Palo Alto, CA, as part of a research agreement. The 
Calypso Anchored beacon transponders received FDA 510(k) clearance. Previously, a 
physician-sponsored investigational device exemption {IDE) application had been approved 
by the Food and Drug administration (FDA) to permit the use of Anchored Beacon 
Transponders in lung for this study. A cross-reference to the IDE for the ongoing Calypso 
feasibility trial which is already on file at the FDA has been kindly provided by Varian Medical 
Systems. 
The SuperDimension ENB and Olympus rEBUS are both in routine use by our lnterventional 
Pulmonology and Thoracic Surgery services including the disposable GuideSheath Extended 
Working Channels (EWC), Locatable Guides (LG), and the planning and navigation software. 
Prior to undergoing treatment, the patient will have a CT chest for Navigation performed at 
MSKCC. The images obtained from this specially formatted CT scan will be uploaded into 

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the SuperDimension iLogic software suite. The lesion of interest will be selected, a 3-D 
airway model created and a pathway(s) to the lesion will be selected and confirmed. This 
"patient plan" will be brought to the operating room for use during the placement of the 
Calypso fiducials, as part of the standard use of the SuperDimension ENB system. The 
following is an outline of the basic schema of how the procedure will be performed: 
 
Bronchoscopic Intervention with Calypso beacon transponder placement: 
 
1. Pre-operative "patient plan" created and confirmed to be appropriate for beacon 
transponder placement 
2. Anesthesia induction via laryngeal mask airway or endotracheal tube 
3. Standard bronchoscopic evaluation of the airways 
4. The LG and EWC are advanced through the working channel of the 
bronchoscope 
5. Registration of the SuperDimension ENB system 3-D model with the airways in 
real time is performed 
6. Navigation of the LG and EWC to the lesion of interest 
7. Flouroscopy to confirm location of EWC and that it does not move during the 
placement of the beacon transponders 
8. Removal of the LG while maintaining the EWC in place 
9. Confirmation with rEBUS that the EWC is at the lesion of interest 
10. Placement of 3 Calypso beacon transponders in or near the lesion of interest under 
fluoroscopic guidance 
11. Fluoroscopic confirmation of placement 
12. Removal of EWC 
13. Final bronchoscopic evaluation of the airways 
14. Emergence from anesthesia with standard post-procedural care, including a 
portable CXR 
During the procedure, all care will be taken to reduce the risk of adverse events for the 
placement of the fiducials. The use of Olympus rEBUS and fluoroscopy, in addition to the 
SuperDimension ENB system, will further reduce the risk of adverse events, including 
pneumothorax. As previously noted, the risk of adverse events during the placement of 
fiducials is very low, with the majority of the risk associated with anesthesia. [37, 46-48, 50]. 
There is an inherent increased risk for these patients since they will have to undergo a 
bronchoscopy for the placement of fiducials as part of the radiation therapy, unlike patients 
who are undergoing radiation therapy without fiducial placement. Since the majority of these 
patients have many medical comorbidities and have been deemed non-operable, a complete 
pre-operative assessment will be performed by either the Thoracic Surgery or Pulmonology 
service, with standard anesthesia evaluation done during pre-surgical testing, to confirm that 
the patient is an acceptable risk for anesthesia. This may include formal cardiac and 
pulmonary studies, as well as appropriate specialty consultations, including internal 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
14 
 
 
medicine, geriatrics or cardiology, at the discretion of the treating physician. If it is 
determined that the risk of anesthesia is too great, the patient will not be eligible for this 
study. 
 
The entire Calypso monitoring system including 4D console, electromagnetic array, tracking 
station and optical system is in place and currently in routine use for prostate cancer 
patients. The linear accelerator is equipped for intensity modulated radiation therapy as is 
used for lung RT and on-board kV imaging. For patients who agree to use the digital 
goggles, the visual feedback of the Calypso signal will be captured by an iPhone that records 
the Calypso signal on the screen. This will be transmitted to a pair of video goggles or an 
iPhone to be viewed by the patient. The visual feedback system is not part of the Calypso device. 
We have successfully tested, on volunteers, the ability of this system to adequately display 
the signal on the viewing device. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
• 
Patients must have histologic proof of malignancy suitable for thoracic radiation therapy 
• 
Patients planning to undergo radiation therapy for primary or recurrent malignancy of the 
lung or metastatic malignancy to the lung. 
Note: this may be delivered by SBRT or standard fractionation, based on the discretion 
of the treating physician. 
• 
Age 
18 years old 
• 
KPS 
60% 
• 
Ability to hold their breath for >20 seconds for 5 times 
• 
Patients who are able to tolerate flexible bronchoscopy 
• 
Patients with life expectancy of at least 12 months 
• 
Patients able to have bronchoscopic placement of Calypso transponders as confirmed on a 
recent (within the past 8 weeks) CT scan. 
• 
Patients who are able to comply with the protocol follow-up schedule. 
 
6.2 
Subject Exclusion Criteria 
 
• 
Patients unable to comply with instructions for DIBH 
• 
Patients with implants in the chest region that contain metal or conductive materials (e.g., 
metal implants, rods, or plates) which Varian Medical considers will interfere with the 
Calypso System's electromagnetic localization. 
• 
Patients with active implanted devices, such as pacemakers, defibrillators, and drug 
infusion pumps since the effects of the Calypso System operation on these devices are 
unknown. 
• 
Patients with clinically significant active infections. 
• 
Patients with bronchiectasis in the region of the intended implantation sites. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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• 
Patients with a history of hypersensitivity to nickel. 
• 
Patients whose lung tumors are being monitored with MR imaging (MR imaging of the 
anchored transponders is safe but yields an image artifact around the anchored 
transponders). 
• 
Posterior lesions that would be >19cm distance from Calypso detector plate. Patients 
may be treated in the prone position in order to meet the required minimum distance. 
• 
Patients with any other medical condition or laboratory value that would, at the discretion 
of the investigator, preclude the patient from participation in this clinical study. 
• 
Patients who are deemed unable to safely undergo or tolerate flexible bronchoscopy 
• 
Patients who are unable to tolerate anesthesia or sedation 
• 
Patients enrolled in any other clinical studies the investigator believes to be in conflict 
with this investigation. 
• 
Female patients who are pregnant or nursing 
 
7.0 
RECRUITMENT PLAN with Limited Waiver of Authorization 
Patients will be evaluated by the attending physician from the Department of Radiation 
Oncology and entered onto the study if they are appropriate. The attending physician, or his 
designate, will obtain informed consent from the patient. 
We have taken notice of NIH/ADAMHA policies concerning the inclusion of women and 
minorities in clinical research populations. We expect that the study population will be fully 
representative of the range of patients seen at MSKCC without exclusion to age (> 18 years), 
or ethnic background. Given the limited number of subjects to be entered onto the study, no 
specific outreach efforts are planned. 
Potential research subjects will be identified by a member of the patient's treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center 
(MSKCC). If the investigator is a member of the treatment team, s/he will screen their 
patient's medical records for suitable research study participants and discuss the study and 
their potential for enrolling in the research study. Potential subjects contacted by their 
treating physician will be referred to the investigator/research staff of the study. 
The principal investigator may also screen the medical records of patients with whom they do 
not have a treatment relationship for the limited purpose of identifying patients who would be 
eligible to enroll in the study and to record appropriate contact information in order to 
approach these patients regarding the possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at MSKCC in order to further assess eligibility. They will 
use the information provided by the patient and/or medical record to confirm that the patient 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
16 
 
 
is eligible and to contact the patient regarding study enrollment. Patients will be asked to 
perform a DIBH maneuver in clinic of five breathholds of 20 seconds each. If the patient turns 
out to be ineligible for the research study, the research staff will destroy all information 
collected on the patient during the initial conversation and medical records review, except for 
any information that must be maintained for screening log purposes. 
The initial contact with the prospective subject will be conducted either by the treatment team, 
investigator or the research staff working in consultation with the treatment team. The 
recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be maintained as part of a screening log. For these 
reason, we seek a limited waiver of authorization for the purposes of (1) reviewing relevant to 
the enrollment process; (2) conversing with patients regarding possible enrollment; (3) handling 
of PHI contained within those records and provided by the potential subjects; and (4) 
maintaining information in a screening log of patients approached (if applicable). 
We expect to accrue 1-2 patients per month for a total of 30 patients. 
8.0 
PRETREATMENT EVALUATION 
 
• 
Pathology review to confirm diagnosis 
• 
History and physical exam 
• 
The DIBH maneuver consists of a comfortably deep inhalation followed by a breath 
hold. Patients will be clinically tested (typically at the time of consultation) to hold their 
breath for a minimum of 20 seconds xS times in a simulated treatment position with 
their arms raised above their heads. The patient will be asked to practice at home, and 
coaching will be repeated at the time of treatment. 
• 
CT scan of the chest for navigation 
• 
Pregnancy test, if applicable 
• 
Consultation with thoracic surgery or interventional pulmonology for transponder 
implantation 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Using ENB and rEBUS, three Calypso transponders will be bronchoscopically placed within a 
small bronchial airway according to the Anchored Beacon Transponder Instructions for Use 
provided by Varian Medical (see section 20.0 Appendices). Two Calypso transponders will be 
permissible if it is technically not possible to place three transponders, as the tracking system 
works with a minimum of two transponders. Placement within 2 cm from the pleura should be 
avoided if possible to minimize the risk of pneumothorax. The position of the anchored 
transponders will be verified by fluoroscopy at the time of placement. 
After a minimum of 3 days, the patient will be brought to the radiation simulation suite and 
immobilized using a custom-mademold, as per our standard protocol. Immobilization will be 
in a supine position unless prone treatment is required to meet the distance requirement 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
17 
 
 
between the Calypso beacons and the Calypso detector plate. The patient will be coached 
through the DIBH maneuver and a breath-hold level that the patient can comfortably and 
reproducibly achieve using the Calypso system will be determined. A free-breathing (FB) 4D 
CT scan of the thorax and a CT scan in DIBH mode will be obtained using the RPM system. 
The patient's position and setup will be documented by tattoos and photographs. 
Target volumes and normal structures will be delineated on the FB scan and on the DIBH 
scan. Target delineations will be performed on the registered 4DCT image set and on the 
DIBH scan as per current clinical practice. The Calypso beacons will also be delineated on 
each phase of the 4DCT study and on the DIBH scans. 
 
Analysis of the 4DCT will provide an initial evaluation of the motion concordance between the 
Calypso beacon and the RPM external marker. Two radiation treatment plans will be 
developed, one based on the free-breathing scan and one based on the DIBH scan. These 
will be used for dosimetric comparison of treatment plans between a free-breathing and DIBH 
treatment. Only the DIBH treatment plan will be used clinically, unless a patient is unable to 
complete the DIBH maneuvers at the time of treatment. In that case, the plan based on the FB 
scan will serve as a backup plan. The beacon coordinates for the DIBH scan will be input to 
the Calypso system. 
 
In the additional 25 patients to be accrued the window will be reduced in a step-wise fashion 
by 1mm for every 5 patients. Number of beam holds, treatment interruptions and total 
treatment time from first beam-on time to the last beam-off time will be recorded by the 
therapists. 
If a patient cannot achieve the desired breath hold after 3 attempts and discussion with the 
therapist, the therapist can treat with the best breath-hold achievable and report the change 
in level to the treating physician. Additionally, the therapist will acquire an orthogonal pair of 
images. The physicist will then estimate the dosimetric effects per day in case the patient is 
still unable to achieve adequate breath hold the next day. Depending on the estimated 
dosimetry and the patient's reasons for not being able to achieve breath hold, the patient 
may be taken off protocol if unable to perform the breath hold to within +/- 5 mm for 3 
consecutive treatment days. Patients who are taken off protocol prior to treatment 
completion will be treated based on the free-breathing treatment planning scan for the 
remainder of the radiation treatment course. 
 
9.1 
For patients undergoing SBRT in 10 or less fractions, the following procedures will be 
performed: 
1. Standard setup procedures based on external tattoos will be performed. 
 
2. The Calypso antenna will be deployed and positioned over the patient's chest. Tracking of 
the Calypso transponder signal will commence. 

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IRB Number: 13-174 A(15) 
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3. For patients who have been selected to use the digital goggles, the DIBH maneuver will be 
performed with visual biofeedback at least once a week and at least one fraction will be done 
without visual feedback. During treatment the radiation therapist will coach the patient on 
how to hold their breath during the treatment. On treatment days with visual feedback, the 
patient will be able to view and control his/her breathing through biofeedback using goggles 
(Myvu Personal Media Viewer, Myvu Corporation) or an iPhone that displays the Calypso 
trace. The couch position will be adjusted by the therapists in the treatment room to 
accurately set up the patient for treatment in DIBH based on the Calypso signal. The Calypso 
trace will be set to zero based on the DIBH level. 
4. The patient will resume regular breathing and the therapists will leave the room. 
 
5. The patient will be remotely asked to repeat the DIBH maneuver and a CBCT will be 
obtained over several breathholds (exact number depending on the patient's ability to hold 
their breath) using partial arcs and the assigned breath hold tolerance window. 
6. The CBCT images will be evaluated and the patient will be repositioned for a soft tissue 
match as needed. The soft tissue match will then be evaluated and approved by the treating 
physician as is our normal clinical process. The isocenter coordinates in Calypso will be 
changed based on the patient's repositioning shift dictated by the CBCT soft tissue match. 
No more than 2 CBCTs per treatment will be done for protocol purposes. 
The patient will then be remotely asked to reproduce the DIBH maneuver with the tolerance 
window to which they have been assigned and be treated in DIBH. Number of beam holds, 
treatment interruptions and total treatment time from first beam-on time to the last beam-off 
time will be recorded by the therapists. Beacon position during DIBH will be monitored by the 
therapist to assure that the patient maintains the DIBH position throughout the treatment 
delivery. If the Calypso beacon signal indicates that the tumor has moved outside of the 
tolerance window, the radiation beam will be automatically held by the system and resumed 
when the target is within range. 
 
 
 
9.2 
For patients undergoing standard fractionated RT the following procedures will be 
performed: 
1. Standard setup procedures based on external tattoos will be performed. 
 
2. The Calypso antenna will be deployed and positioned over the patient's chest. Tracking of 
the Calypso transponder signal will commence. 
Optional: In patients where the Calypso antenna external markers detected by an in-house 
infrared tracking system can be arranged in such a way that both signals can be obtained 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
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19 
 
 
simultaneously (depending on body habitus), a free-breathing trace of the Calypso 
transponders over 2 minutes in combination with the external marker signal will be obtained . 
These will be used for future analysis and building of an external/internal respiration model. 
3. For patients who have been selected to use the digital goggles, the DIBH maneuver will be 
performed with visual biofeedback at least once a week and at least one fraction will be done 
without visual feedback .During treatment the radiation therapist will coach the patient on how 
to hold their breath during the treatment. On treatment days with visual feedback, the patient 
will be able to view and control his/her breathing through biofeedback using goggles (Myvu 
Personal Media Viewer, Myvu Corporation) or an iPhone that displays the Calypso trace. The 
couch position will be adjusted by the therapists in the treatment room to accurately set up 
the patient for treatment in DIBH based on the Calypso signal. The Calypso trace will be set 
to zero based on the DIBH level. 
 
4. The patient will resume regular breathing and the therapists will leave the room. 
 
5. The patient will be remotely asked to repeat the DIBH maneuver and a set of orthogonal kV 
images will be obtained. These will be used to verify that no beacon has migrated from its 
initial position. 
7. Once a week, the patient will be remotely asked to repeat the DIBH maneuver and a CBCT 
will be obtained over several breathholds (exact number depending on the patient's ability to 
hold their breath) of 15 seconds each using partial arcs and the assigned breath hold 
tolerance window. No more than 8 weekly imaging sessions with CBCT will be done for 
protocol purposes. 
8. The CBCT images will be evaluated and the patient will be repositioned for a soft tissue 
match as needed. The soft tissue match will then be evaluated and approved by the treating 
physician. The isocenter coordinates in Calypso will be changed based on the patient's 
repositioning shift dictated by the CBCT soft tissue match. 
 
The patient will then be remotely asked to reproduce the DIBH maneuver with a tolerance 
window to which they have been assigned and be treated in DIBH Number of beam holds, 
treatment interruptions and total treatment time from first beam-on time to the last beam-off 
time will be recorded by the therapists. Beacon position during DIBH will be monitored by the 
therapist to assure that the patient maintains the DIBH position throughout the treatment 
delivery. If the Calypso beacon signal indicates that the tumor has moved outside of the 
tolerance window, the radiation beam will be automatically held by the system and resumed 
when the target is within range. For treatments between CBCT sessions, the patient will be 
set up according to steps 1-4, kV images will be acquired (Step 5) to verify beacon stability 
and the day's treatment with breath-hold will proceed without further imaging. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 

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Physician evaluation of patient setup accuracy will be performed using all available images 
and adjustments will be made as per standard practice. In addition, the Calypso signal will 
be used to verify and monitor the patient's DIBH maneuver. Should the transponder signal 
indicate that the target has moved outside of the preset tolerance, radiation treatment 
delivery will be held until the patient's breathhold has returned to the desired target range or 
until the patient's setup has been corrected. 
Patients will return for follow up at 3, 6, 9 and 12 months(+/- 4 weeks) following 
completion of radiation therapy. Data from any clinical followups between 12 and 24 
months following completion of radiation therapy(+/- 4 weeks) will be collected 
retrospectively through a retrospective research protocol. The following assessments will 
be performed at these visits: history and physical exam, diagnostic CT chest, and toxicity 
assessment. The history and physical exam may be completed in the medical oncology 
clinics for patients who experience progression of disease. In this case, the toxicity 
assessment will be completed over the phone with the treating radiation oncologist. 
 
 
Pre- 
treatment 
Simulation 
Radiation 
Treatment 
(SBRT) 
Radiation 
Treatment 
(standard 
fractionation) 
Follow-up 
3, 6, 9 
and 12 
months 
History & physical 
X 
X 
Pregnancy test 
(if applicable) 
X 
Evaluation for 
DIBH fitness 
X 
Beacon 
implantation 
X 
CT scan for 
navigation 
X 
Free-breathing scan 
X 
4DCT 
X 
DIBH CT 
X 
Set-up 
X 
X 
Calypso signal 
recording 
X 
X 
RT with DIBH with or 
without visual 
feedback 
X 
X 
Daily Orthogonal 
KV images 
X 
Weekly CBCT (up 
to 8) 
X 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
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Daily CBCT (up to 2 
CBCTs per fraction 
for protocol 
purposes) 
X 
Diagnostic CT 
chest 
X 
X 
Toxicity 
assessment 
Weekly 
during 
treatment 
Weekly 
during 
treatment 
X 
 
 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Patients will be monitored for study-related toxicities according to CTCAE v4.0. Only side 
effects that are possibly, probably or definitely related to the protocol therapy and grades 2-5 will 
be documented. This includes the following toxicities: 
 
1. Potential side effects related to anesthesia: 
a. Hypotension 
b. Arrhythmia 
c. Respiratory failure 
2. Potential side effects related to flexible bronchoscopy: 
a. Sore throat 
b. Post-extubation bronchospasm 
c. Throat or chest tightness 
3. Potential side effects related to the implantation and/or the fiducial markers: 
a. Bronchopleural fistula 
b. Lung or airway damage 
c. Bleeding 
d. Fever 
e. Hemoptysis 
f. Respiratory infection / pneumonia 
g. Lung Infection 
h. Pneumothorax 
i. 
Cough 
j. Dyspnea 
k. Fiducial embolization 
I. 
Migration of fiducial markers 
4. Potential side effects related to radiation therapy: 
a. Fatigue 
b. Cough 

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c. Dyspnea 
d. Pneumonitis 
e. Dysphagia 
f. Esophagitis 
g. Nausea 
h. Vomiting 
i. Diarrhea 
j. Anorexia 
k. Dehydration 
I. 
Radiation dermatitis 
m. Respiratory infection / pneumonia 
 
Abnormal laboratory values, regardless of grade, will not be reported. Toxicities of 
treatments that are not associated with the protocol therapy (i.e. chemotherapy-related 
side effects) will not be graded nor attributed. 
 
Only toxicities communicated directly to, and reviewed by, the treating physician or study 
Pl, and deemed possibly, probably or definitely related to the protocol treatment will be 
documented. 
 
A clinical study summary can be found at: http://oncology.varian.com/calypsolungstudy 
 
DEFINITIONS 
 
1. Definition of an Adverse Event (AE) 
a.  An Adverse Event is defined by the GCP (Guide to Good Clinical Practice) as any 
undesirable experience occurring to a subject during a clinical trial, whether or not 
it is considered related to the investigational product(s). 
 
2. Definition of a Serious Adverse Event (SAE) 
a. A Serious Adverse Event is an adverse experience that: 
i. is fatal or life-threatening 
ii. is disabling 
iii. results in hospitalization or prolongation of hospitalization 
iv. results in a congenital anomaly or occurrence of malignancy 
 
b.  Any neurologic and musculoskeletal toxicity that is grade 3 or higher will be 
considered a serious adverse event. 

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c. Only serious adverse events that are at least possibly related to the 
investigational product will be reported as the radiation therapy is 
considered standard of care. 
3. Definition of an Unexpected Adverse Event 
 
a. An Unexpected AE is an experience not previously reported (in nature, severity, 
or incidence) in the current Investigator's Brochure or general investigational plan. 
Evaluation of SAE: 
Review of the patient record including the treatment dosimetry will be undertaken by the 
principal investigator. The principal investigator may decide to continue the protocol without 
modification, discontinue the study altogether, or to modify the protocol prior to enrolling more 
patients pending the results of the review. However, if the SAE meets the criteria for the 
stopping rule, as defined in Section 14.0, the trial will be stopped. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Primary objectives: 
 
• To evaluate the feasibility of Calypso transponders as an internal tumor surrogate to guide 
DIBH radiation treatments in real time. 
 
•  Feasibility is defined as completion of all treatments using the DIBH treatment plan and 
Calypso transponders. Patients who cannot have their transponders placed accurately 
bronchoscopically or for whom Calypso-guided DIBH will not be possible will be considered 
a failure. Patients who are removed from the protocol as a result of being unable to perform 
the breath hold for 3 consecutive treatment days at any point in the treatment course for 
reasons that are not related to the Calypso transponders, Calypso detection or 
complications of using the Calypso implantation or system (e.g. disease progression, severe 
side effects from treatment, e.g. esophagitis, infections, failure to thrive, generalized 
weakness, low blood counts etc.), will be replaced by new evaluable patients. Those 
patients will be treated with the free-breathing backup radiation treatment plan. The reason 
for the patient's inability to hold their breath will be recorded. 
Secondary objectives: 
 
• 
To compare the reproducibility with visual versus without visual biofeedback. 
• 
To assess differences in the ability of maintaining the DIBH maneuver within the fate with 
and without visual biofeedback 
• 
To measure the residual intrafraction tumor motion and associated improvement in 
normal tissue dosimetry during DIBH based on the Calypso lung transponder signal as a 
surrogate 

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• 
To measure the increase in dose escalation and the potential for decreasing margins 
made possible by Calypso-guided DIBH 
• To determine the minimum clinically feasible gate margin for radiation 
• To assess tumor shrinkage, beacon position and centroid changes in conventionally 
fractionated patients 
• To assess intra- and inter-fraction variation in lung volume preservation of multiple DIBH 
maneauvers 
Reproducibility of using internal tumor surrogates (Calypso beacons) during repeated deep 
inspiration breath hold maneuvers with and without visual biofeedback will be evaluated by 
posthoc analysis of the Calypso signal traces. The ability to maintain the breathhold to within 
the tolerance level to which they have been assigned will be assessed. Number of beam holds 
and treatment interruptions will be recorded as an objective measure of the patient's ability to 
maintain their breathhold. Whether or not visual biofeedback will aid in the ability to hold their 
breath reliably and within the target region will be assessed using the number of treatment 
interruptions. We will also assess differences in duty cycle and number of DIBH attempts with 
and without visual biofeedback. Differences in the ability of maintaining the DIBH maneuver 
within the gate with and without visual biofeedback will be measured as duty cycle, a 
quantifiable measure of how long it takes to deliver a radiation treatment. It is related to how 
well patients can hold their breath and the tumor in the target position. Each patient will have 
the goggles 50% of the treatments and without goggles the other 50% of the time. Wilcoxon 
rank sum tests will be done to compare the duty cycle. 
The residual intrafraction motion and drift during DIBH will be determined based on the 
Calpyso signal traces which may provide critical insight into the ability to immobilize the 
tumor by DIBH. Beacon position stability will be determined on acquired cone-beam CTs by 
measuring the distance of the beacons to the center of the gross target volume {GTV) as well 
as the distance of the beacons to each other. Improvement of normal tissue dosimetry based 
on Calypso-guided DIBH will be determined from the treatment plans developed on the free­ 
breathing and DIBH simulation CT scans. Specific dosimetric parameters will include the chest 
wall V30, total lung V20, mean lung dose, lung toxicity model metrics (Lyman model NTCP 
and parallel model fraction damaged (fdam)), mean and maximum esophageal dose, and 
maximum spinal cord dose. 
 
To determine the minimum clinically feasible gate margins we will decrease the gate in a 
step-wise progression as far as a minimum of 2 mm. The gate will be reduced from +/- 
5mm by 1mm for every 5 patients treated. Halving of the duty cycle will be considered the 
minimum gate that is clinically feasible. Once the minimum gate is determined, the 
remaining patients will be treated at +1mm from this value. 
 
In the additional 10 conventionally fractionated patients, tumor shrinkage will be 
summarized as relative shrinkage in a percentage. Beacon position and centroid are 3D 
coordinates that will be determined as a distance from a landmark such as a bone or the 
carina. 

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Lung volume preservation will be assessed on wide field of view cone-beam CTs and 
compared intra- and interfraction within each patient to check for reproducibility or 
variability of lung volumes across multiple DIBH maneuvers. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
1. Found to be ineligible for the protocol as described in the section on Criteria for 
Patient/Subject Eligibility 
2. Patient and/or guardian requests to withdraw from study for any reason 
3. Referring physician requests to withdraw from study for any reason, including believing 
that it would be in the patient's best interest 
4. Refusal of patient to continue treatment and/or observations 
5. Loss to follow-up 
6. Patient death 
7. Calypso beacon migration of >5cm from original implantation position may be taken off 
study if the Calypso signal can no longer be detected 
8. Patient unable to adequately perform the breath hold for 3 consecutive treatment days 
 
 
Acquired data from patients who would be removed from the protocol after a portion of the 
treatment has been completed can be used for analysis. 
 
14.0 
BIOSTATISTICS 
 
The primary objective of this nonrandomized study is to test the feasibility of anchored Calypso 
transponders to guide and monitor DIBH radiation treatments. Feasibility is defined as patients being 
able to successfully complete the course of treatment. Patients who cannot have their transponders 
placed accurately bronchoscopically and for whom Calypso-guided DIBH will not be possible as a 
consequence of that will be considered a failure. Patients who are removed from the protocol as a 
result of being unable to perform the breath hold for 3 consecutive treatment days at any point in the 
treatment course for reasons that are not related to the Calypso transponders, Calypso detection or 
complications of using the Calypso implantation or system (e.g. disease progression, severe side 
effects from treatment, e.g. esophagitis, infections, failure to thrive, generalized weakness, low blood 
counts etc.), will be replaced by new evaluable patients. The patients who are removed will be treated 
with the free-breathing backup radiation treatment plan. The reason for the patient's inability to hold 
their breath will be recorded. 
 
For this objective the first and second set of 25 evaluable patients will be stratified and analyzed 
separately. Some details are provided below. 
We will enroll 30 patients upfront and we expect that at least 25 evaluable (DIBH training can be 
done and Calypso beacons can be implanted without migrating > 5cm) patients can be used in 

Memorial Sloan Kettering Cancer Center 
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assessing the feasibility rate. To establish the decision rule we will compute the sample feasibility 
rate (i.e., the number of patients who could be successfully treated divided by the total number of 
evaluable patients, which we expect to range from 25 to 30) and form an 80% 2-sided Clopper­ 
Pearson exact confidence interval. If the lower bound of this exact confidence interval is greater than 
66% then we will declare this procedure feasible. Namely, we will test the hypotheses Ho: 9<=0.66 
vs. H1: 9>0.66 at alpha=0.05, where 9 denotes the feasibility rate. The test statistic will be the lower 
bound of the 90% 2-sided Clopper-Pearson exact confidence interval for binomial trials. Equivalently, 
this test statistic can be written as Beta(0.05, X, N+1-X), i.e., the 5th-percentile of the beta distribution 
with two parameters X and N+1-X, where X and N denote the number of successes and the total 
sample size (expected to be from 25 to 30), respectively. When the sample size is as small as 25, 
the power of rejecting the null hypothesis is 61%, 84% and 97% when the true feasibility rate is 0.80, 
0.85 and 0.90, respectively. When the sample size is as large as 30, such power becomes 61%, 85% 
and 97%. Since we expect the feasibility rate to be around 0.85, the sample size is sufficiently large. 
We expect to finish the recruitment in 4 years. 
 
For protective purposes we will implement a stopping rule to prevent excessive rate of pneumothorax 
or hospitalization (related to the proposed procedure). If 6 or more events (i.e., procedure-related 
pneumothorax or hospitalization) among the first 30 patients, or 11 or more events among the total 
55 patients we plan to enroll are observed, we will halt the trial to thoroughly investigate such events. 
This sequential stopping rule has the following probability of halting the trial: 
 
True event probability 
I
0.05 I 
0.08 I 
0.10 
0.15 
0.20 
0.25 
0.30 
Probability of halting the trial I
0.003I 0.030I 0.081 
0.342 
0.679 
0.900 
0.978 
 
In addition, a second stopping rule will be implemented if a maximum of two device migrates to a 
critical organ, such as the heart or brain, or if one device-related death is observed. 
 
For the 1st secondary objective, we will compare the visual vs no visual biofeedback treatments (for 
patients who agree to use the digital goggles) by the number of treatment interruptions. We expect 
that there will be fewer treatment interruptions when using biofeedback. To this end Wilcoxon 
signed-rank tests will be conducted based on the patients who can successfully be treated. 
 
For the 2nd secondary objective, we will assess differences in the ability of maintaining the DIBH 
maneuver within the fate with and without visual biofeedback. Such differences will be measured 
as duty cycle, and will be compared using Wilcoxon signed-rank tests based on the patients who 
can successfully be treated. 
 
For the 3rd secondary objective, the residual intrafraction tumor motion (surrogated by Calypso) will 
be measured in all 3 dimensions and the euclidean distance will be calculated, which will then be 
correlated with the normal tissue dosimetry (see end of Section 12.0). Patients will receive multiple 
fractions and thus multiple measurements of such distance will be obtained from the same patients. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
27 
 
 
These repeated measures will be averaged for each patient and the correlation will be examined by 
simple linear regression. If such continuous data are skewed, we may either use an appropriate 
monotone transformation, or examine the nonparametric correlation coefficient (such as Spearman 
rank correlation coefficient) between the tumor motion and the normal tissue dosimetry instead. 
 
For the 4th secondary objective, the potential increase in dose escalation and decrease in margins 
made possible by Calypso- guided DIBH, as contrasted to those obtained from the 40 CT scan, will 
be formulated as pair data from each patient and tested by using Wilcoxon signed-rank tests. 
Dosimetric parameters listed at the end of Section 12.0 will be used again for such analysis. 
 
The 5th secondary objective does not require statistical analysis. See Section 12.0 for details. 
 
For the 6th secondary objective, tumor shrinkage, beacon position and centroid changes in 
conventionally fractionated patients (totally 10), all measured as continuous variables, will be 
summarized descriptively. 
 
For the 7th secondary objective, intra- and inter-fraction variation in lung volume preservation of 
multiple DIBH maneauvers will be recorded within each patient and summarized descriptively. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming that the participant is eligible to enroll in the study. Study staff are responsible 
for ensuring that all institutional requirements necessary to enroll a participant to the study 
have been completed. See related Clinical Research Policy and Procedure #401 (Protocol 
Participant Registration). 
 
15.2 
Randomization 
No randomization will occur in this study. 
 
16.0 
DATA MANAGEMENT ISSUES 
A Clinical Research Coordinator (CRC) and/or Clinical Research Associate (CRA) will be 
assigned to the study. The responsibilities of the CRC or CRA include project compliance, 
data collection, abstraction and entry, data reporting, regulatory monitoring, problem 
resolution and prioritization, and coordination of the activities of the protocol study team. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
28 
 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 
Regular registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled "Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials" which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase Ill 
clinical trials, report to the Center's Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Risks: There are small risks of side effects related to the implantation of the Calypso 
transponders into small airways near the tumor or the tumor itself. These risks include but 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
29 
 
 
are not limited to fever, bleeding, airway obstruction, pneumothorax, device embolization, 
device migration and pneumonia. Radiation exposure due to additional protocol imaging is 
minimal. Doses required for kV conebeam imaging are on the order of 3-4 cGy per scan; 
doses for standard radiographic imaging are less than 0.1 cGy /image. 
 
Costs: All of the treatments, studies, and procedures are considered standard of care, 
including the placement of standard fiducials for radiation therapy. The patient and/or 
patient's insurance will be responsible for all charges, which are part of the standard of care. 
No financial reimbursement or other financial incentive will be provided for patients to enroll in 
this study. The Calypso beacons will be provided by Varian and are research non-billable. 
The implantation of the beacons will be billable to insurance. Any complications from the 
Calypso beacon implantation will be managed as per responsible physician and any tests or 
interventions related to the management of potential complications will be billed to the 
patient's insurance. Performing the placement of the Calypso beacon transponders in the 
context of a clinical trial will allow for a more indepth and objective evaluation of the system. 
 
Benefits: There is a potential clinical benefit from this clinical trial in terms of decreased 
toxicity from radiation treatments and/or achieving a higher total treatment dose due to DIBH. 
We hope that in the future, knowledge from this trial will help patients that are candidates for 
the implantation of Calypso transponders as well as patients who are not candidates by 
improving our understanding of real-time tumor position changes with respiration. 
 
Side effects: Side effects of the study specific to the implantation of the fiducial markers are 
anesthesia risk, bleeding, infection, pulmonary toxicities, and migration of the fiducial 
markers. 
 
17.1 
Privacy 
MSKCC's Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant's name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified researchers. 
 
17.2 
Serious Adverse Event (SAE) Reporting 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
30 
 
 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse event 
• 
 An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 
• 
 Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant's last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
 
Please note: Any SAE that occurs prior to the start of investigational 
treatment/intervention and is related to a screening test or procedure (i.e., a screening 
biopsy) must be reported. 
 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
31 
 
 
per IRB SOP RR-408 'Reporting of Serious Adverse Events', the SAE report must be 
submitted within 5 calendar days of the event. All other SAEs must be submitted within 
30 calendar days of the event. 
 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant's condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
17.2.1  
Not applicable 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-174 A(15) 
Approval date: 26-Dec-2023 
32 
 
 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
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35 
 
 
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20.0 
APPENDICES 
 
Appendix 1: 
Patient Instructions: Beacon care package- Lung instructions