The goal of this trial is to see if this investigational drug is safe for adult patients with melanoma that has spread to other parts of the body or cannot be removed by surgery. It will also see if this investigational drug can shrink melanoma tumors in the body. The main questions this study aims to answer are:

• What are the side effects of this investigational drug?
• What is the highest dose of this investigational drug that can be given safely?

Participants will:

• Take the investigational drug once every 6 weeks, for up to 6 times in total
• Visit a doctor's office on a regular basis for checkups and tests

This is a multicenter, open-label Phase 1-1b study of [225Ac]Ac-A9-3408 in subjects with unresectable or metastatic melanoma.

The primary aim of the Phase 1 portion of the study is to evaluate the safety and tolerability as well as the normal organ and tumor dosimetry of [225Ac]Ac-A9-3408 and to select a recommended Phase 2 dose (RP2D).

The aim of Phase 1b will be to evaluate the safety, efficacy, and normal organ and tumor dosimetry of [225Ac]Ac-A9-3408 administered at the RP2D in subjects with unresectable or metastatic cutaneous melanoma who had confirmed disease progression while receiving an anti-PD-1/PD-L1-containing regimen.

The interventional diagnostic [68Ga]Ga-A9T-3202 will be administered intravenously (IV) once during screening.

The interventional drug [225Ac]Ac-A9-3408 will be administered intravenously (IV) once every 6 weeks, for a total of up to 6 cycles.

Inclusion Criteria:

• Able to provide written informed consent
• [68Ga]Ga-A9T-3202 uptake in at least one measurable lesion (per RECIST v1.1) on PET scan
• Histologically or cytologically confirmed unresectable or metastatic melanoma with disease progression on prior standard of care therapy
• Adequate ECOG performance status
• Adequate baseline organ function within 14 days of first dose of investigational product
• Recovered from side effects of prior anticancer therapy
• Women of childbearing potential (WOCBP) must have a negative pregnancy test and follow adequate birth control method(s) during the treatment period and for at least 6 months after last dose of [225Ac]Ac-A9-3408. Sexually active males with partners who are WOCBP must agree to adequate birth control method(s) during the treatment period and for at least 3 months after last dose of [225Ac]Ac-A9-3408

Exclusion Criteria:

• Previous treatment with radioactive nuclides except radioactive imaging tracers
• Treatment with another investigational product shortly prior to first dose of [225Ac]Ac-A9-3408 with exception of anti-PD-1/PD-L1 agents.
• Concurrent anticancer therapy
• Major surgery within 4 weeks of first dose of investigational product
• Second malignancy within 2 years
• Active, clinically serious infection
• Known infusion reactions to components of the investigational product
• Other clinically serious health conditions including cardiovascular and or severe infectious diseases
• Significant central nervous system metastatic disease
• Pregnant, breastfeeding or unwilling to practice adequate birth control method(s)
• Any condition per the opinion of the investigator that would impact the safety of the subject, protocol adherence or ability to provide informed consent