Background: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [¹³¹I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [¹³¹I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. Methods: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [¹³¹I]ICF01012 (185 MBq at D0) to select patients who might benefit from [¹³¹I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [¹³¹I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m², or 1600 MBq/m², or 2700 MBq/m² or 4000 MBq/m² of [¹³¹I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [¹³¹I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [¹³¹I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. Discussion: This study is a first-in-human trial evaluating the [¹³¹I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [¹³¹I]ICF01012 to select the patients who may benefit from a therapeutic dose of [¹³¹I]ICF01012, with at least one tumor lesion with [¹³¹I]ICF01012 uptake and an acceptable AD to healthy organ. Trial registration: Clinicaltrials.gov: NCT03784625. Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

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