Intratumoral Targeted Hyperthermia Therapy (THT) for Stage 3C/3D/4M1 Cutaneous Metastatic Melanoma

This phase I/II device clinical trial investigates the safety and efficacy of GNR-mediated THT in patients with stage 3C/3D/4M1 cutaneous metastatic melanoma unresponsive to systemic checkpoint immunotherapy or in patients who have contraindications to systemic immunotherapy.

The primary objective of the study is to evaluate the safety of THT treatment, with secondary objectives focused on tumor response to treatment.

Patients will receive intra-tumoral GNR injections, followed by NIR light therapy to induce mild hyperthermia, with intra-tumoral temperatures monitored to achieve a target range of 42°C to 48°C. The trial aims to establish a safe, effective dose of GNRs for THT therapy for cutaneous metastatic melanoma treatment and explore the potential for its localized tumor destruction.


Eligibility Criteria:
Inclusion Criteria:

* 16 years of age or older
* Participants with histologically or cytologically confirmed stage 3C/3D/4M1 advanced or cutaneous metastatic melanoma, with measurable disease by iRECIST including any number of cutaneous lesions
* Present a visible and accessible primary tumor or metastatic deposit (any site) that has not been surgically removed
* Present target tumors of 0.5 -2.5 cm in diameter
* Participants must have received and failed systemic and local intra-tumoral therapy at least one prior standard therapy, including immune checkpoint inhibitors (e.g., anti- PD1 or anti-CTLA-4), and failed local intra-tumoral IL-2 treatment. Failed response to treatment will be categorized according to iRECIST guidelines.
* Participants who have:

  * Immune partial response (iPR): At least a 30% decrease in the sum of diameters of target lesions compared to baseline, no progression of non-target lesions, No new lesions
  * Immune Stable Disease (iSD): Neither sufficient reduction to qualify for iPR nor sufficient increase to qualify for iCPD (immune confirmed progressive disease), no new lesions
  * Immune Unconfirmed Progressive Disease (iUPD); At least a 20% increase in the sum of diameters of target lesions, taking the smallest sum on study as the reference, appearance of new lesions, iUPD needs confirmation after at least 4 weeks; if confirmed, it becomes iCPD
  * Immune Confirmed Progressive Disease (iCPD): iUPD must be confirmed in a follow-up assessment (minimum of 4 weeks after initial iUPD), if progressive disease (increase in lesion size or additional new lesions) is still evident upon re-evaluation, iCPD is confirmed.
* Participants must agree to discontinue treatment with local intralesional immunotherapies during the study, with resumption after completion of the trial
* ECOG Performance Status:
* Life expectancy: ≥6 months
* Participants able and willing to provide written informed consent and comply with the trial protocol. 10. Either BRAF positive (BRAF+) or BRAF negative (BRAF-)

Exclusion Criteria:

* Women who are pregnant, breastfeeding, or planning to become pregnant during the study.
* Women of childbearing potential must have a negative pregnancy test within 72 hours prior to enrollment and agree to use adequate contraception throughout the study
* Any infection requiring systemic therapy or other concurrent medical conditions (e.g., hepatitis B, hepatitis C, HIV) that would interfere with the study
* Myocardial infarction or stroke within the past 6 months, uncontrolled angina, or significant arrhythmia
* Participants receiving blood thinners as part of therapeutic anticoagulation therapy
* Any severe or uncontrolled comorbid condition that, in the investigator's opinion, would pose excessive risk to the participants (e.g., immunodeficiencies, severe hypertension, uncontrolled diabetes, liver failure)
* Participation in another clinical trial involving an investigational product/device within 30 days prior to screening
* Any condition that would impede compliance with study procedures
* Participants with a known allergy to gold of any kind
* Participants who are unable to tolerate cutaneous injections for any reason will not be eligible
* Participants with a known allergy to injectable local analgesics
* Participants with ocular melanoma or melanoma involving periorbital skin.