Feasibility Study of Using Navigational Bronchoscopy to Perform PDT-Photofrin® in Unresectable Peripheral Lung Cancer

Lung cancer accounts for almost one-third of cancer deaths. Cancer screening strategies have the potential to achieve a 20% reduction in death rates. Newly developed bronchoscopic technologies (such as navigational bronchoscopy) have shown to enable physicians to safely reach lesions in peripheral regions of the lung and obtain diagnosis. This new technology may now potentially offer bronchoscopic therapeutic interventions, such as photodynamic therapy, to tumors that were previously unreachable due to their peripheral anatomic location.

Photodynamic therapy (PDT) uses a combination of a photosensitizing drug (a drug that is activated by light), called porfimer sodium (Photofrin®), and a light from a laser that emits no heat. This technique works to allow the medical doctor to specifically target and destroy abnormal or cancer cells while limiting damage to surrounding healthy tissue. The activation of the drug is done by lighting the abnormal area using a fiber optic device (very fine fiber \[like a fishing line\] that permits light transmission) inserted into a flexible tube called bronchoscope. The light activates the porfimer sodium, which is concentrated in the abnormal tissue, leading to its destruction.

The purpose of this study is to determine if physicians can reach the tumors in the periphery of the lung via electronavigational bronchoscopy and deliver the photodynamic therapy by placing the optical fiber into the tumor.

• Porfimer sodium (Drug), also known as Photofrin: After injection of porfimer sodium (Photofrin®), a flexible bronchoscopy with navigation guidance will be performed to confirm the location and the size of the lesion with the use of radial probe endobronchial ultrasonography (REBUS). A light dose of 200 J/cm of diffuser length will be delivered.
• Fiber optic (Device): A fiber optic diffuser length matching the tumor length will be placed in the lesion under fluoroscopy guidance.

Primary outcomes

• Feasibility to Perform Interstitial-Photodynamic Therapy (i-PDT) Into Tumor [Day 3 post-treatment]: Number of times photodynamic therapy was delivered into the tumor using navigational bronchoscopy for each subject.
• Adverse Events Incidence Indicating Safety of Navigational Bronchoscopy-interstitial-Photodynamic Therapy (i-PDT) [Up to 6 months]: The incidence of adverse events following navigational bronchoscopy-iPDT (interstitial-Photodynamic Therapy) will be presented as the primary safety indicator for this treatment.

Secondary outcomes

• Tumor Response at 3 Months Post Photodynamic Therapy (PDT) [Up to 3 months]: From the start of treatment until 3 months post-treatment measured as per the Modified RECIST (Response Evaluation Criteria in Solid Tumors) Criteria
• Tumor Response at Study Exit (6 Months) Post Photodynamic Therapy (PDT) [Up to 6 months]: From the start of treatment until 6 months post-treatment measured as per the Modified RECIST (Response Evaluation Criteria in Solid Tumors) Criteria
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Screening (Days -14 to -1). Baseline. [up to day 0 (-14 to -1 days)]: Measured at screening to be the baseline measure. The Eastern Cooperative Oncology Group (ECOG) scores range from 0 to 5. The lowest values mean a better outcome: 0 is fully active with no performance restrictions; 1 is strenuous physical activity restricted but fully ambulatory and able to carry out light work; 2 is capable of all self-care but unable to carry out any work activities - up and about >50% of waking hours; 3 is capable of only limited self-care and confined to bed or chair >50% of waking hours; and 4 is completely disable, cannot carry out any self-care and totally confined to bed or chair.
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Day 1 (Date of Photofrin Injection). [1 day]: Measured at Day 1 which is day of the photofrin injection. The Eastern Cooperative Oncology Group (ECOG) scores range from 0 to 5. The lowest values mean a better outcome: 0 is fully active with no performance restrictions; 1 is strenuous physical activity restricted but fully ambulatory and able to carry out light work; 2 is capable of all self-care but unable to carry out any work activities - up and about >50% of waking hours; 3 is capable of only limited self-care and confined to bed or chair >50% of waking hours; and 4 is completely disable, cannot carry out any self-care and totally confined to bed or chair.
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Day 3 (Day of Photodynamic Therapy) [Day 3]: Measured at Day 3. The Eastern Cooperative Oncology Group (ECOG) scores range from 0 to 5. The lowest values mean a better outcome: 0 is fully active with no performance restrictions; 1 is strenuous physical activity restricted but fully ambulatory and able to carry out light work; 2 is capable of all self-care but unable to carry out any work activities - up and about >50% of waking hours; 3 is capable of only limited self-care and confined to bed or chair >50% of waking hours; and 4 is completely disable, cannot carry out any self-care and totally confined to bed or chair.
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Day 30 (30 Days Post Photofrin Injection) [Day 30]: Measured at Day 3. The Eastern Cooperative Oncology Group (ECOG) scores range from 0 to 5. The lowest values mean a better outcome: 0 is fully active with no performance restrictions; 1 is strenuous physical activity restricted but fully ambulatory and able to carry out light work; 2 is capable of all self-care but unable to carry out any work activities - up and about >50% of waking hours; 3 is capable of only limited self-care and confined to bed or chair >50% of waking hours; and 4 is completely disable, cannot carry out any self-care and totally confined to bed or chair.
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at 3 Months Post Photofrin Injection [up to 3 months]: Measured at 3 months. The Eastern Cooperative Oncology Group (ECOG) scores range from 0 to 5. The lowest values mean a better outcome: 0 is fully active with no performance restrictions; 1 is strenuous physical activity restricted but fully ambulatory and able to carry out light work; 2 is capable of all self-care but unable to carry out any work activities - up and about >50% of waking hours; 3 is capable of only limited self-care and confined to bed or chair >50% of waking hours; and 4 is completely disable, cannot carry out any self-care and totally confined to bed or chair.
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at 6 Months Post Photofrin Injection [Up to 6 months]: Measured at 6 months. The Eastern Cooperative Oncology Group (ECOG) scores range from 0 to 5. The lowest values mean a better outcome: 0 is fully active with no performance restrictions; 1 is strenuous physical activity restricted but fully ambulatory and able to carry out light work; 2 is capable of all self-care but unable to carry out any work activities - up and about >50% of waking hours; 3 is capable of only limited self-care and confined to bed or chair >50% of waking hours; and 4 is completely disable, cannot carry out any self-care and totally confined to bed or chair.
• Short Form Health Survey (SF-36) Score at Baseline [Baseline]: The Short-Form Health Survey (SF-36) scores range from 0 to 100, with higher scores indicating better health status. SF-36 evaluates 9 dimensions of Health: physical function, role limitations due to physical health problems, body pain, general health, vitality, social functioning, role limitations due to emotional problems domain, and mental health. Summary is provided in the form of physical component score (PCS) and mental component score (MCS) for each of the timepoints.
• Short-Form Health Survey (SF-36) Score at Follow-up Visit at 3 Months. [up to 3 months]: The Short-Form Health Survey (SF-36) scores range from 0 to 100, with higher scores indicating better health status. SF-36 evaluates 9 dimensions of Health: physical function, role limitations due to physical health problems, body pain, general health, vitality, social functioning, role limitations due to emotional problems domain, and mental health. Summary is provided in the form of physical component score (PCS) and mental component score (MCS) for each of the timepoints.
• Short-Form Health Survey (SF-36) Score at Study Exit (6 Month Visit) [Up to 6 months]: The Short-Form Health Survey (SF-36) scores range from 0 to 100, with higher scores indicating better health status. SF-36 evaluates 9 dimensions of Health: physical function, role limitations due to physical health problems, body pain, general health, vitality, social functioning, role limitations due to emotional problems domain, and mental health. Summary is provided in the form of physical component score (PCS) and mental component score (MCS) for each of the timepoints.
• Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 Item (QLQ-C30): Baseline [Baseline]: Baseline score of EORTC QLQ-C30 which is a multi-dimensional Health Related Quality of Life measure designed for use in lung cancer patients. Includes 5 functional measures (physical, role, emotional, social, cognitive), 8 symptoms (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea) and global health status and financial impact. Most items use 4-item scale from "not at all" to "very much". Raw scores are transformed to 0-100 scale with higher scores representing better functioning/Quality of Life and greater symptom burden.
• Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 Item (QLQ-C30): Follow-up 3 Months [up to 3 months]: 3 month score of EORTC QLQ-C30 which is a multi-dimensional Health Related Quality of Life measure designed for use in lung cancer patients. Includes 5 functional measures (physical, role, emotional, social, cognitive), 8 symptoms (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea) and global health status and financial impact. Most items use 4-item scale from "not at all" to "very much". Raw scores are transformed to 0-100 scale with higher scores representing better functioning/Quality of Life and greater symptom burden.
• Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 Item (QLQ-C30): 6 Months [Up to 6 months]: 6 month score of EORTC QLQ-C30 which is a multi-dimensional Health Related Quality of Life measure designed for use in lung cancer patients. Includes 5 functional measures (physical, role, emotional, social, cognitive), 8 symptoms (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea) and global health status and financial impact. Most items use 4-item scale from "not at all" to "very much". Raw scores are transformed to 0-100 scale with higher scores representing better functioning/Quality of Life and greater symptom burden.
• Health-related Quality of Life on the 4- Point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Lung Cancer 13 Item (QLQ-LC13): Baseline Score [Baseline]: Baseline measure for EORTC QLQ-LC13 which is a 13-item lung cancer-specific questionnaire module. It is used in conjunction with the QLQ-C30. It is comprised of multi-item and single-item measures of lung cancer associated symptoms (coughing, hemoptysis, dyspnea, pain) and side effects from conventional chem-and radiotherapy (alopecia, neuropathy, sore mouth, dysphagia). For these symptom-oriented scales, a higher score means more severe symptoms. The scale is from 1 (not at all) to 4 (very much). The scoring (as reported here) is from 0 to 100 with the higher score meaning a more severe symptom.
• Health-related Quality of Life on the 4- Point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Lung Cancer 13 Item (QLQ-LC13): Follow-up 3 Month Score [up to 3 months]: 3-Month measure for EORTC QLQ-LC13 which is a 13-item lung cancer-specific questionnaire module. It is used in conjunction with the QLQ-C30. It is comprised of multi-item and single-item measures of lung cancer associated symptoms (coughing, hemoptysis, dyspnea, pain) and side effects from conventional chem-and radiotherapy (alopecia, neuropathy, sore mouth, dysphagia). For these symptom-oriented scales, a higher score means more severe symptoms. The scale is from 1 (not at all) to 4 (very much). The scoring (as reported here) is from 0 to 100 with the higher score meaning a more severe symptom.
• Health-related Quality of Life on the 4- Point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Lung Cancer 13 Item (QLQ-LC13): Study Exit (6 Months) Score [Up to 6 months]: 6-Month measure for EORTC QLQ-LC13 which is a 13-item lung cancer-specific questionnaire module. It is used in conjunction with the QLQ-C30. It is comprised of multi-item and single-item measures of lung cancer associated symptoms (coughing, hemoptysis, dyspnea, pain) and side effects from conventional chem-and radiotherapy (alopecia, neuropathy, sore mouth, dysphagia). For these symptom-oriented scales, a higher score means more severe symptoms. The scale is from 1 (not at all) to 4 (very much). The scoring (as reported here) is from 0 to 100 with the higher score meaning a more severe symptom.
• Number of Participants With Indicated Adverse Events [Up to 6 months post-treatment]: Adverse events (AEs) noted by number of participants with at least one event. An AE was defined as any untoward medical occurrence in a subject during the course of the study, regardless of causal relationship. AEs were coded using MedDRA Version 21.1
• Number of Subjects With at Least One Serious Adverse Event [Up to 6 months]: The number of subjects with at least one serious adverse event are listed.
• Safety: Physical Examination Summaries for Each Subject [Up to 6 months]: Safety evaluation will include the physical examinations summary of non-normal findings for each subject.
• Safety: Number of Participants With Indicated Vital Sign Summaries [Up to 6 months]: Safety evaluation included vital sign summary for each subject. Vital signs included pulse, blood pressure, temperature and respiration rate. Only clinically relevant results, as per the investigator judgement, are included. These would be vital signs that are out of the normal range but could be considered outside enough to be clinically relevant to the subject's health.
• Safety: Number of Participants With Indicated Changes to Pulmonary Function Tests (PFTs) Related to Treatment Emergent Adverse Events [Up to 6 months]: The treatment emergent adverse events related to PFTs are noted. Pulmonary function test measurements were: Diffusion Capacity of Lung for Carbon Monoxide (%), Expiratory Reserve Volume (mL), Forced Vital Capacity (mL), Forced Expiratory Volume in 1 second (mL), Forced Expiratory Flow 25% to 75% (L/min), Functional Residual Capacity (mL), Maximum Voluntary Ventilation (L/min), Residual Volume (mL), Peak Expiratory Flow (L/min), Slow Vital Capacity (mL), Total Lung Capacity (mL)
• Safety: Laboratory Test Summaries for Each Subject [Up to 6 months]: Safety evaluation includes laboratory tests summarized for each subject with any abnormal lab results considered an Adverse Event to be listed. The investigators commented on any laboratory value outside the normal reference range. If the value was judged to be an Adverse Event, it is listed. The values analysed were: Hematology (Hemoglobin, Hematocrit, White Blood Cell, Red Blood Cell, Platelet Count, Prothrombin Time) and Chemistry (Glucose (random), Blood Urea Nitrogen, Electrolytes (sodium, potassium, chloride), Creatinine, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Albumin, Total Protein)

Other outcomes

• Immunology Markers Concentrations Were Examined as an Exploratory Endpoint. The Change From Baseline Was Reported. [Baseline, 10 days post-treatment]: Distribution of lymphocyte subsets from peripheral blood was determined by flow cytometry. Flow cytometry is a laser-based technique used to detect and measure physical and chemical characteristics of a population of cells or particles. It allows simultaneous multi-parameter analysis of single cells. The selected markers of interest, representative of the broader markers were: Total Thymus-cells (T-Cells), Cluster of Differentiation 4 (CD4) T cell subsets, and Cluster of Differentiation 9 (CD8) T cell subset, CD4 T Regulatory (T Reg) cells, Natural Killer Cells, Activated T cells, Myeloid-Derived Suppressor Cells (MSCDs), Monocytes. The Percent Gated and Absolute counts were analysed for each marker. Gating allows the analysis to be restricted to a specific size of cells (e.g. lymphocytes) to allow a more specific analysis. Absolute counting quantifies the total number of cells. It is recommended to look at both values to get the full picture.
• Skin Photosensitivity as a Adverse Event of Special Interest: Participants With Event [Up to 6 months]: Adverse Event of special interest was Skin Photosensitivity. Skin photosensitivity was examined because all subjects who receive Photofrin are photosensitive and must observe precautions to avoid exposure of eyes and skin to direct sunlight or bright indoor lights for 30 days or longer. Changes in skin will be assessed by grade of erythema, edema and blistering and will be tabulated by Common Terminology Criteria for Adverse Events (CTCAE) grade in the dermatology/skin category.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or female aged 18 or older
* Diagnosed with histologically confirmed solid tumor located in the peripheral lung
* Not candidate for curative surgery, is unfit for surgery, or does not wish to undergo curative surgery
* May be candidate for, have failed, or does not wish to undergo radiation therapy
* The tumor is ≤ 3 cm in size and clearly observable in computerized tomography (CT scan)
* Able to sign an informed consent

Exclusion Criteria:

* Diagnostic of small cell lung cancer
* Solid tumor located in central lung
* Presence of concurrent non-solid malignancy
* Abnormal blood results
* Received chemotherapy/immunotherapy in the last 4 weeks
* Tumor invades a major blood vessel
* Porphyria or known hypersensitivity to Photofrin® or porphyrin-like compounds or to any of its excipients
* Planned surgical procedure within the next 90 days
* Coexisting ophthalmic disease likely to require slit-lamp examination within the next 90 days
* Acute or chronic medical or psychological illnesses that prevent endoscopy procedures
* Pregnant or intend to become pregnant, breastfeeding or intend to breastfeed during the study
* Received PDT during the past 3 months
* Severe impairment of your kidney or liver function
* Participates or intends to participate in another drug study (other than observational studies) during the study

Participant flow

Outcome results

• Feasibility to Perform Interstitial-Photodynamic Therapy (i-PDT) Into Tumor (Primary), Count of participants, Participants: Photodynamic Therapy-Photofrin 3
• Adverse Events Incidence Indicating Safety of Navigational Bronchoscopy-interstitial-Photodynamic Therapy (i-PDT) (Primary), Count of participants, Participants: Photodynamic Therapy-Photofrin 5
• Tumor Response at 3 Months Post Photodynamic Therapy (PDT) (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 1
• Tumor Response at Study Exit (6 Months) Post Photodynamic Therapy (PDT) (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 1
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Screening (Days -14 to -1). Baseline. (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 1
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Day 1 (Date of Photofrin Injection). (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 1
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Day 3 (Day of Photodynamic Therapy) (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 0
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at Day 30 (30 Days Post Photofrin Injection) (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 1
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at 3 Months Post Photofrin Injection (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 2
• Performance Status on the Eastern Cooperative Oncology Group (ECOG) Score at 6 Months Post Photofrin Injection (Secondary), Count of participants, Participants: Photodynamic Therapy-Photofrin 3
• Short Form Health Survey (SF-36) Score at Baseline (Secondary), Median, score on a scale: Photodynamic Therapy-Photofrin 49.27 +/- 6.71
• Short-Form Health Survey (SF-36) Score at Follow-up Visit at 3 Months. (Secondary), Median, score on a scale: Photodynamic Therapy-Photofrin 46.83 +/- 5.60
• Short-Form Health Survey (SF-36) Score at Study Exit (6 Month Visit) (Secondary), Median, score on a scale: Photodynamic Therapy-Photofrin 48.33 +/- 7.45
• Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 Item (QLQ-C30): Baseline (Secondary), Mean, score on a scale: Photodynamic Therapy-Photofrin 55.0 +/- 28.62
• Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 Item (QLQ-C30): Follow-up 3 Months (Secondary), Mean, score on a scale: Photodynamic Therapy-Photofrin 70.0 +/- 17.29
• Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 Item (QLQ-C30): 6 Months (Secondary), Mean, score on a scale: Photodynamic Therapy-Photofrin 71.66 +/- 20.07
• Health-related Quality of Life on the 4- Point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Lung Cancer 13 Item (QLQ-LC13): Baseline Score (Secondary), Mean, score on a scale: Photodynamic Therapy-Photofrin 39.98 +/- 24.36
• Health-related Quality of Life on the 4- Point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Lung Cancer 13 Item (QLQ-LC13): Follow-up 3 Month Score (Secondary), Mean, score on a scale: Photodynamic Therapy-Photofrin 40.0 +/- 24.37
• Health-related Quality of Life on the 4- Point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Lung Cancer 13 Item (QLQ-LC13): Study Exit (6 Months) Score (Secondary), Mean, score on a scale: Photodynamic Therapy-Photofrin 40.0 +/- 30.04
• Number of Participants With Indicated Adverse Events (Secondary), Number, Participants with at least one event: Photodynamic Therapy-Photofrin 1
• 7 more outcome measures not shown.

Adverse events

Time frame: 6 months for each subject. The study was conducted over a period of 1 year and 5 months in total (29Nov2017 to 12Apr2019)

Other adverse events by term

Limitations and caveats: Early termination of the study lead to small numbers of subject being analysed.

• Study Protocol and Statistical Analysis Plan (PDF, 2017-10-26)

• Michelle Depot, Ph.D., Study director, at the request of Concordia Laboratories Inc.