Radiation dosimetry of [<sup>131</sup>I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment

Jouberton, E.; Perrot, Y.; Dirat, Béatrice; Billoux, Tommy; Auzeloux, Philippe; Cachin, F.; Chezal, Jean‐Michel; Filaire, Marc; Labarre, P.; Miot-Noirault, Élisabeth; Millardet, C.; Valla, C.; Vidal, Aurélien; Degoul, Françoise; Maigne, Lydia

doi:10.1002/mp.13165

Cited by 7 publications

(7 citation statements)

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“…NRAS Q61K 1007 tumors clearly accumulate a sufficient amount of [ 131 I]ICF01012 to improve the efficiency of TRT, with an absorbed dose in the supra-therapeutic range (94 Gy), as the curative dose for EBRT is 50 to 60 Gy. The extrapolated dosimetry to humans does not suggest major toxicity, as the absorbed doses of non-target organs remained within the recommended limits, as previously reported for extrapolated doses from a rabbit bio-distribution study [50]. The main concern with TRT using [ 131 I]ICF01012 is potential ocular toxicity due to a high absorbed dose related to [ 131 I]ICF01012 fixation on the melanin present in the choroid and retinal pigment epithelium.…”

Section: Discussionsupporting

confidence: 70%

“…The main concern with TRT using [ 131 I]ICF01012 is potential ocular toxicity due to a high absorbed dose related to [ 131 I]ICF01012 fixation on the melanin present in the choroid and retinal pigment epithelium. However, [ 131 I]ICF01012 rabbit dosimetry extrapolated to humans has shown that the absorbed dose in the eyes remains acceptable [50]. Furthermore, the first clinical trial using a similar radiolabeled melanin-binding molecule showed clear clinical improvement for 2 of 5 patients with metastatic melanoma and did not report any ocular toxicity [51].…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Akil

Quintana

Raymond

et al. 2021

Cancers

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Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Akil

Quintana

Raymond

et al. 2021

Cancers

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“…A precise dosimetry, i.e. the quantification of energy deposed in tumour and non-target organs, is the main concern for TRT evaluation in a clinical trial [ 21 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Radiotoxicity studies conducted with [ 131 I]ICF01012 at a therapeutic dose on highly pigmented mouse models have shown a transient decrease in white blood cells and a relative decrease in the thickness of the retina [ 22 ]. Dosimetry extrapolations have shown retina-values below the maximum tolerated doses, suggesting that this ocular specific targeting is not expected to have an impact in human [ 23 ]. Furthermore, preliminary toxicological studies point out that TRT with [ 131 I]ICF01012 was compatible with clinical requirements.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol

et al. 2022

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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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“…Rabbits (New Zealand male rabbits weighing 2.5–3.0 kg) were injected with a solution of 99m Tc- PHH or 99m Tc- MPHH in PBS (7–7.5 MBq, 300 μL). The rabbits were anesthetized and sacrificed ( n = 3 rabbits per group) at 15 min p.i., a part of the organs of interest were dissected and weighed . The radioactivity uptake in the organs was measured using a γ-counter and calculated as the percentage injected activity/g of each sample (% IA/g).…”

Section: Experimental Sectionmentioning

confidence: 99%

Synthesis and Biological Evaluation of ^99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

et al. 2021

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With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HT 7 Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as PHH and MPHH were designed, and the corresponding radiotracers 99m Tc-PHH and 99m Tc-MPHH were synthesized in high radiochemical purity (>95%). 99m Tc-MPHH showed a higher affinity to 5-HT 7 Rs on U-87 MG cells compared to 99m Tc-PHH. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to 99m Tc-MPHH, the 99m Tc-PHH exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of 99m Tc-MPHH led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT 7 receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of 99m Tc-PHH and 99m Tc-MPHH in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.

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Radiation dosimetry of [¹³¹I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment

Abstract: This study sustains [ I]ICF01012 as a good candidate for melanoma TRT and open perspectives for personalized dosimetry calculation during phase I clinical transfer.

Cited by 7 publications

References 45 publications

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol

Synthesis and Biological Evaluation of ^99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

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Radiation dosimetry of [131I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment

Abstract: This study sustains [ I]ICF01012 as a good candidate for melanoma TRT and open perspectives for personalized dosimetry calculation during phase I clinical transfer.

Cited by 7 publications

References 45 publications

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol

Synthesis and Biological Evaluation of 99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

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Radiation dosimetry of [¹³¹I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment

Synthesis and Biological Evaluation of ^99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging