Irradiation of Melanoma in a Pulse

Study Overview
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Brief Summary
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This is a single center phase I, first-in-human, dose escalation study of FLASH therapy in patients with metastases of melanoma. The trial is based on escalating single doses of FLASH therapy administered to skin melanoma metastases using the Mobetron® with high dose rate (HDR) functionality. The aim of the study is to evaluate a dose escalation of high dose rate radiotherapy (FLASH therapy) as single dose treatment for skin melanoma metastases that progress locally despite systemic treatments. Melanoma is a typically radio-resistant tumor type, which can justify such a dose escalation with a new type of radiotherapy that appears much better tolerated than conventional radiotherapy.

Official Title
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A Phase I, First-in-human, Dose Finding Study of High Dose Rate Radiotherapy in Patients With Skin Metastases From Melanoma

Conditions
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Metastasis From Malignant Melanoma of Skin (Diagnosis)

Intervention / Treatment
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* Device: FLASH therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed study Informed Consent Form Karnofsky Performance Status (KPS) ≥ 50 Age ≥ 18 years Patients with metastatic melanoma and multiple skin metastases with a documented clinical progression despite the systemic treatments (chemotherapy, and/or Programmed cell death 1 (PD1), cytotoxic T-lymphocyte antigen-4 (CTLA4) inhibitors or tyrosine kinase inhibitors (TKIs), such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) or mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors) The size of the treated lesions should be ≤ 5.5 cm in diameter and ≤ 2.8 cm thick (caliper-based measurement) The treated lesions should be at least 5 cm apart and must not be located on the face. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (urine or serum) during screening WOCBP must use a contraceptive method Exclusion Criteria: Previous radiotherapy in the treated area Concomitant auto-immune disease with skin lesions Concomitant use of radio-sensitizer drug Women who are pregnant Current, recent (within 10 days prior start of study treatment), or planned participation in an experimental drug study. During the 4 weeks DLT period, the patient will not be able to participate to any other clinical study. Any serious underlying medical condition that could interfere with study treatment and potential adverse events Any mental or other impairment that may compromise compliance with the requirements of the study

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: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation of FLASH therapy in skin metastases of small volume (≤ 30 cc)<br>7 dose levels (22 Gy; 24 Gy; 26 Gy; 28 Gy, 30 Gy, 32 Gy and 34 Gy) | Device: FLASH therapy<br>* Dose escalation of high dose rate radiotherapy (FLASH therapy) as single dose treatment for skin melanoma metastases that progress locally despite systemic treatments.<br>* Other names: high dose rate radiotherapy;|
| Experimental: Dose escalation of FLASH therapy in skin metastases of large volume (> 30 and ≤ 100 cc)<br>7 dose levels (22 Gy; 24 Gy; 26 Gy; 28 Gy, 30 Gy, 32 Gy and 34 Gy) | Device: FLASH therapy<br>* Dose escalation of high dose rate radiotherapy (FLASH therapy) as single dose treatment for skin melanoma metastases that progress locally despite systemic treatments.<br>* Other names: high dose rate radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of maximum tolerated dose (MTD) or recommended phase II dose (RP2D), separately for skin metastases of small and large volumes. | Acute safety (dose limiting toxicity, DLT) of the high dose rate radiotherapy (RT) procedure (for each dose level) will be evaluated during the 4 weeks post-treatment using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0). | from Day 1 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with Hemorrhage related to the treated lesions, assessed visually by the investigator | Hemorrhage will be visually assessed (presence/abscence) | At each visit, from screening to 12 months post-treatment | 
| Percentage of patients with Skin ulceration related to the treated lesions, assessed visually by the investigator | Skin ulceration will be visually assessed (presence/abscence) | At each visit, from screening to 12 months post-treatment | 
| Percentage of patients with Pain related to the treated lesions, assessed with analogic visual pain scale | Pain will be assessed using an analogic visual pain scale (score from 1 to 10) | At each visit, from screening to 12 months post-treatment | 
| Local response of metastases in the radiation field, measured with calipers | Irradiated lesions will be measured with calipers. Local response of metastases in the radiation field will be calculated as rate over all treated lesions and will be compared between small versus large volume lesions within each dose level. | At screening, Day 1, at weeks 1, 3, 4, and 6 post-treatment; at months 3, 6, and 12 post-treatment; and at local progression | 
| Frequency of Late side effects observed in radiation field |  | ≥ 6 months post-treatment | 
| Blinded Imaging Central Review (BICR) of photographs evaluating both tumor response and in radiation field normal tissue responses around the treated tumors | A baseline photograph will be taken the day of the treatment in a pre-therapeutic setting with skin delineation of the lesion. Then photos will be repeated at 1 (+/-2d), 3 (+/-2d), 4 (+/-3d), 6 (+/-3d) weeks after treatment, then at 3 (+/-7d), 6 (+/-14d), 12 (+/-14d) months and at progression. | From Day 1 up to 12 months post-treatment | 
| Optical coherence tomography (OCT) examination of the irradiated skin compared to the normal non-irradiated skin | Epidermis thickness and roughness; plexus depth; number and size of vessels; number and size of hairs, will be compared between irradiated skin and normal non-irradiated skin | at 4 weeks, 6 months and 12 months post-treatment | 
| Frequency of late adverse events (within 12 months post-treatment) for each dose | Long-term safety of RT procedure will be measured as recording of late adverse events (CTCAE v5.0) | within 12 months post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLASH therapy, melanoma