Intratumoral Targeted Hyperthermia Therapy (THT) for Cutaneous Metastatic Melanoma

Intra-tumoral Targeted Hyperthermic Therapy (THT) for Stage 3C/3D/4M1 Cutaneous Metastatic Melanoma in Patients With Targetable Cutaneous and/or Sub-cutaneous Tumors

This device phase I/II, first in human, early feasibility study (EFS), open-label, single-arm trial aims to evaluate the safety, tolerability, and preliminary efficacy of Gold Nanorod (GNR)-enabled sub-ablative targeted hyperthermia therapy (THT) in patients with unresectable stage 3C/3D/4M1 cutaneous metastatic malignant melanoma that have failed to respond to systemic checkpoint and localized intra-tumoral immunotherapy. The study will involve up to 10 participants with stable or progressive cutaneous and/or subcutaneous skin lesions (Immune Stable Disease (iSD) or Immune Confirmed/Unconfirmed Progressive Disease (iCPD/iUPD)).

GNRs, when administered via intra-tumoral injection and activated by NIR light, generate localized heat through a process called THT. This approach selectively targets tumor cells while minimizing damage to surrounding healthy tissue. In this study, 10 participants will receive two THT treatments spaced 7 days apart.

The primary objective of this study is to assess the safety and tolerability of THT treatment.

Inclusion Criteria:

1. 16 years of age or older;
2. Participants with histologically or cytologically confirmed stage 3C/3D/4M1 advanced or cutaneous metastatic melanoma, with measurable disease by iRECIST 1.1 criteria, including any number of cutaneous lesions;
3. Present a visible and accessible primary tumor or metastatic deposit (any site) that has not been surgically removed;
4. Present target tumors of ≤2.5 cm in diameter;
5. 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. Patients who have: a) 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; or b) 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; or c) 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; or d) 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.
6. Participants must agree to discontinue treatment with local intralesional immunotherapies during the study, with resumption after completion of the trial;
7. ECOG Performance Status: ≤1;
8. Life expectancy: ≥6 months;
9. 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:

1. 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;
2. Any infection requiring systemic therapy or other concurrent medical conditions (e.g., hepatitis B, hepatitis C, HIV) that would interfere with the study;
3. Myocardial infarction or stroke within the past 6 months, uncontrolled angina, or significant arrhythmia;
4. Participants receiving blood thinners as part of therapeutic anticoagulation therapy;
5. 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);
6. Participation in another clinical trial involving an investigational product/device within 30 days prior to screening;
7. Any condition that would impede compliance with study procedures;
8. Participants with a known allergy to gold of any kind;
9. Participants who are unable to tolerate cutaneous injections for any reason will not be eligible;
10. Participants with a known allergy to injectable local analgesics;
11. Participants with ocular melanoma or melanoma involving periorbital skin.