TOtal Skin Electron Beam Therapy (Low-dose) for Tumor Clone Eradication in Early-stage Mycosis Fungoides

Study Overview
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Brief Summary
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Primary cutaneous T-cell lymphomas are a group of peripheral T-cell lymphomas that primarily involve the skin. Mycosis fungoides (MF) is the most frequent subtype. Most patients with early-stage MF (i.e., patches and plaques of the skin without extracutaneous involvement) have a good prognosis but a subset of patients progress to incurable advanced-stage disease with an overall survival (OS) less than 5 years and an impaired quality of life. We have recently identified the tumor clone frequency in lesional skin (measured by high-throughput sequencing of the TCRB locus) as the most important prognostic factor of progression-free survival (PFS) and OS in a retrospective analysis on 210 patients with early-stage MF (p<0.001). Phototherapy is a standard therapeutic option in early-stage MF but fails to eradicate the tumor clone from the skin. Low-dose total-skin electron-beam therapy (LDTSEBT, 12 Gy over a 3-week period) has been shown to be safe and highly effective in MF with an 88% overall response rate and a better safety profile compared to standard-dose total-skin electron-beam therapy, in a pooled analysis from 3 phase II trials on 33 patients and a retrospective analysis of 12 patients treated with LDTSEBT. We hypothesize that the use of LDTSEBT is associated with a significantly higher 1-year PFS compared to conventional treatment with phototherapy. Our secondary hypotheses are that LDTSEBT is associated with a higher tumor T-cell clone eradication compared to phototherapy, and improves OS and quality of life in patients with skin-limited MF. The main objective of this study is therefore to prospectively determine if LDTSEBT is associated with a higher 1-year progression-free survival in patients with early-stage mycosis fungoides, compared to conventional treatment with phototherapy. The primary endpoint is PFS at 12 months after study inclusion.

Official Title
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TOtal Skin Electron Beam Therapy (Low-dose) for Tumor Clone Eradication in Early-stage Mycosis Fungoides: a Prospective Randomized Controlled Study

Conditions
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Mycosis Fungoides, Cutaneous T Cell Lymphoma

Intervention / Treatment
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* Other: Low-dose total-skin electron-beam therapy
* Other: Phototherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Histopathologically confirmed diagnosis of International Society for Cutaneous Lymphomas (ISCL) / European Organisation for Research and Treatment of Cancer (EORTC) mycosis fungoides stage IB or IIA Exclusion Criteria: Poor performance status: WHO performance status score > 2 Physically unable to maintain the posture Patient with no health coverage Patient under guardianship or curatorship Previous history of dose-limiting radiation therapy in the field Previous history of dose-limiting phototherapy Previous history of melanoma, skin squamous cell carcinoma or basal cell carcinoma or other absolute contraindication to phototherapy (including a history of lupus, xeroderma pigmentosum, or porphyria) Pregnant or breastfeeding woman Contraindication to methoxsalen (severe liver, renal or heart failure)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Low-dose total-skin electron-beam therapy<br>Low-dose total skin electron beam therapy (12 Gy) will be delivered to the patient in 4 Gy/week, 1 Gy/day over 3 weeks by symmetrical electron beams of 6 MeV energy via a linac accelerator. | Other: Low-dose total-skin electron-beam therapy<br>* Low-dose total skin electron beam therapy (12 Gy) will be delivered to the patient in 4 Gy/week, 1 Gy/day over 3 weeks by symmetrical electron beams of 6 MeV energy via a linac accelerator.<br>|
| Other: Phototherapy<br>Phototherapy will be given 3 times a week during 2 months, then twice a week during one month, then once a week during one month, or until disease progression or unacceptable side effect, whatever comes first. Patients with plaques will receive PUVA therapy and patients with patches only will receive narrow-band UVB therapy. | Other: Phototherapy<br>* Phototherapy will be given 3 times a week during 2 months, then twice a week during one month, then once a week during one month, or until disease progression or unacceptable side effect, whatever comes first. Patients with plaques will receive PUVA therapy and patients with patches only will receive narrow-band UVB therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression will be defined clinically as >25% increase in the modified Severity Weighted Assessment Tool (mSWAT) score from baseline or progression to advanced stage, according to the ISCL/EORTC criteria , or the onset of a new treatment of MF (excepted the use of topical corticosteroids, which is allowed during the study, and will not be considered as a new treatment | at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with tumor clone eradication in skin | Tumor clone eradication in skin will be defined by >90% reduction in the tumor cell content (tumor cells/100 ng DNA by high throughput sequencing of TCRB in a lesional skin biopsy) in skin | at 4 months after inclusion | 
| Complete response rate | Complete response rate will be assessed using ISCL/EORTC criteria | at 4 months after inclusion | 
| Overall response rates | Overall response rate will be assessed using ISCL/EORTC criteria | at 4 months after inclusion | 
| Progression-free survival | Progression will be defined clinically as >25% increase in the modified Severity Weighted Assessment Tool (mSWAT) score from baseline or progression to advanced stage, according to the ISCL/EORTC criteria , or the onset of a new treatment of MF (excepted the use of topical corticosteroids, which is allowed during the study, and will not be considered as a new treatment | at 5 years post inclusion | 
| Overall survival |  | at 5 years post inclusion | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at inclusion | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 1 month | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 4 months | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 1 year | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 2 years | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 3 years | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 4 years | 
| Quality of life as measured by the EORTC QLQ-C30 | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at 5 years | 
| Quality of life as measured by the Skindex scale | Quality of life evaluated using questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning. A high score for the global health status/ QoL represents a high QoL and a high score for a symptom scale/item represents a high level of symptomatology/problems. | at inclusion | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 1 month | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 4 months | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 1 year | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 2 years | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 3 years | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 4 years | 
| Quality of life as measured by the Skindex scale | Quality of life will be measured by the Skindex scale-29 instruments which Measure the Effects of Skin Disease on Quality of Life The Skindex-29 scale is a three-dimensional,dermatology-specific health related quality of life (HRQL) questionnaire. thirty items are combined to form three domains: symptoms,emotions, and functioning. The overall score are expressed on a 100-point scale. A higher scores indicate lower level of quality of life. | at 5 years | 
| Proportion of patients with side effects | Evaluated by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | up to 5 years |