A phase I/IIa of 212PbVMT01 targeted a-particle therapy for unresectable or metastatic melanoma.

TPS9610 Background: Melanoma is an aggressive skin cancer with potential to metastasize early in disease development. Unresectable and metastatic melanoma accounts for 12% of cases and, despite recent advances in treatment, 5-year overall survival for this disease remains low at 35%. The melanocortin 1 receptor (MC1R) is highly expressed in melanoma with low expression in normal tissues and is therefore a target for radiopharmaceutical therapy. We developed 212 PbVMT01, a MC1R-targeting peptide conjugated to a lead-specific chelator. Targeted therapy with 212 Pb has the potential to be efficacious due to the high relative biological effectiveness of α-particles emitted upon its decay. The short physical half-life of 212 Pb (10.6 h) and fast tumor targeting and clearance properties of 212 PbVMT01 can achieve highly efficient delivery of α-particles to MC1R-expressing cancers while sparing healthy tissues. We hypothesize that 212 PbVMT01 can be safely administered to patients with metastatic or unresectable melanoma and can enable disease control. Methods: This is an open-label, multi-center, dose-escalation/dose expansion, phase I/IIa clinical trial evaluating the safety, tolerability, pharmacokinetics, and efficacy of 212 PbVMT01 (NCT05655312). Phase I of the trial follows a mTPI-2 design. The first two cohorts incorporate dosimetry, where participants receive up to 925 MBq or 278 MBq of the therapeutic surrogate 203 PbVMT01 or 68 GaVMT02, respectively, prior to receiving treatment cycles. In these participants, SPECT/CT or PET/CT imaging is obtained up to 24 hours post-injection. Up to 3 treatment cycles of 212 PbVMT01, co-administered with renal protective amino acids, are given 8 weeks apart, with a dose-limiting toxicity observation period of 6 weeks. The cohort 1 dose was 111 MBq, while the ongoing cohort 2 utilizes 185 MBq. Eligibility criteria include MC1R+ disease as determined by SPECT or PET, melanoma stage III or IV and progressive disease by RECIST 1.1. Study participants must have progressed on at least one prior SOC therapy. As part of the study, CT and/or MRI, and FDG PET are acquired at baseline, during, and at the end of treatment. Safety is assessed weekly during cycle 1 and bi-weekly for subsequent cycles. The total in-trial follow-up period is 18 months following final administration of drug. Efficacy is assessed by RECIST 1.1 criteria. The primary objectives are evaluation of the safety of 212 PbVMT01, determination of the maximum tolerated or maximum feasible dose, and determination of the anti-tumor efficacy of 212 Pb. All primary, secondary, and exploratory objectives’ data will be collected for all participants. An interim futility evaluation may be performed after ~10 participants in the dose escalation phase for participants who have completed their first post-treatment response assessment. The trial is open for recruitment. Clinical trial information: NCT05655312 .