A phase I dose escalation of FLASH radiotherapy in patients with cutaneous metastases from melanoma: The IMPulse trial.

Abstract

The observation in preclinical studies that FLASH radiotherapy (FLASH-RT) can spare normal tissues while maintaining its anti-tumoral effect provided the rational for its clinical translation. In this context, this clinical trial presents the first-in-human dose-escalation trial of FLASH-RT. This phase I clinical trial enrolled patients presenting progressive melanoma with cutaneous metastases refractory to systemic treatment. A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD), starting at 22 Gy and escalating in 2 Gy increments up to 28 Gy. Dose-limiting toxicity (DLT) was defined as any Grade ≥ 3 adverse event occurring in the irradiated field within 4 weeks post-RT. FLASH-RT was delivered using a 9 MeV Mobetron (IntraOp, USA) at a dose rate exceeding 200 Gy/s, delivered in 10 pulses over 90 ms. For all patients, dosimetry was performed using alanine, thermoluminescent dosimeters (TLD), and films. Between June 2021 and September 2024, 11 patients were enrolled, with 15 lesions treated in 10 out of these patients. One patient was enrolled at two different dose levels for distinct lesions. The trial initially aimed to dose escalation up to 34 Gy but was discontinued after completing of dose level 28 Gy due to slow accrual. No DLTs were observed at any of the administered dose levels (22-28 Gy), and the MTD was not reached. Dose escalation of FLASH-RT delivered in a single fraction up to 28 Gy did not induce DLTs in the irradiation field, indicating a favorable tolerance of human tissue to the acute effects of FLASH-RT.