Au-TMP and Radiotherapy for Advanced Melanoma With Anti-PD-1 Therapy

Official title

Safety and Tolerability of Au-TMP Nanoparticles in Combination With Radiotherapy for Patients With Advanced Melanoma Receiving Anti-PD-1 Therapy

Overview

Advanced melanoma is a highly aggressive malignancy that frequently exhibits resistance to conventional radiotherapy and single-agent immunotherapy. This study aims to evaluate the safety and tolerability of an innovative melanoma-specific aggregable gold nanosystem (Au-TMP) in patients with advanced melanoma. This single-arm, open-label, Phase 1a clinical trial utilizes a dose-escalation design, where participants receive a single intratumoral injection of Au-TMP followed by sequential radiotherapy and Toripalimab (anti-PD-1) treatment. This trial aims at assessing the safety of intratumoral injection of Au-TMP and radiotherapy in combination with anti-PD-1 therapy.

Detailed description

Overcoming radioresistance and enhancing the clinical efficacy of immune checkpoint inhibitors remain significant challenges in the treatment of advanced melanoma. Au-TMP nanoparticles serve as an innovative radiosensitizing platform engineered based on the specific enzymatic characteristics of the melanoma microenvironment, enabling in situ aggregation and prolonged intratumoral retention to significantly amplify the local cytotoxic effects of radiation through physical energy deposition. This study employs a scientifically structured sequential administration protocol: an ultrasound- or Computed Tomography (CT)-guided intratumoral injection, fractionated radiotherapy (30 Gy in 5 fractions), and commencement of systemic anti-PD-1 therapy. This regimen is designed to facilitate the capture of tumor-associated antigens by Au-TMP and induce immunogenic cell death (ICD), thereby potentially reversing the immunosuppressive microenvironment. Ultimately, this research aims to evaluate the safety and tolerability of this combination approach while assessing preliminary clinical efficacy in patients with advanced melanoma.

Interventions

• Drug Au-TMP
  A single intratumoral injection of Au-TMP (at concentrations of 50 mg/mL using escalating dose levels of 5% or 10% of tumor volume)
• Radiation Fractionated Radiotherapy (RT)
  Local radiotherapy (RT) delivered to the injected tumor lesion, with a total dose of 30 Gy delivered in 5 fractions (6 Gy per fraction).
• Drug Toripalimab
  Administration of Toripalimab (anti-PD-1 antibody) at a fixed dose of 240 mg, administered every 2 weeks (Q2W).

Primary outcome measures

• Incidence of Dose-Limiting Toxicities (DLTs) [Time frame: From the administration of Au-TMP (Day 1) through Day 28.]

Secondary outcome measures (3)

• Incidence and Severity of Adverse Events (AEs) [Time frame: Up to 12 months from the date of Au-TMP administration.]
• Pharmacokinetic (PK) Parameters [Time frame: Day 1 (pre-injection, 1h, 2h, 4h, 8h, 24h post-injection), and Days 4, 8, 15, 28.]
• Objective Response Rate (ORR) [Time frame: Baseline up to disease progression or up to 12 months from the date of Au-TMP administration]

Eligibility criteria

Inclusion criteria

• Age: Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically confirmed unresectable Stage III or Stage IV melanoma without prior systemic therapy. Prior adjuvant or neoadjuvant therapy is permitted, provided it was completed at least 3 weeks before enrollment and all related adverse events (AEs) have resolved to baseline or NCI CTCAE v5.0 Grade ≤ 1.
• Presence of at least one measurable lesion according to RECIST v1.1 criteria.
• At least one lesion suitable for intratumoral injection and radiotherapy (located in the skin, subcutaneous tissue, superficial lymph nodes, or visceral lesions assessed as safe for access) that has not received prior radiotherapy (unless documented progression has occurred).
• Adequate hematologic and organ function within 7 days prior to the first dose, including:

Hematology: Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L; Platelet count (PLT) ≥ 90 × 10⁹/L; Hemoglobin (Hb) ≥ 90 g/L. (No Granulocyte-Colony Stimulating Factor (G-CSF), platelet transfusion, or Erythropoietin (EPO)/Red Blood Cell (RBC) transfusion within 14 days prior to testing).

Renal Function: Serum creatinine (Cr) ≤ 1.5 × Upper Limit of Normal (ULN), or calculated creatinine clearance (Ccr) ≥ 50 mL/min using the Cockcroft-Gault formula.

Hepatic Function: Total bilirubin (TBIL) ≤ 1.5 × ULN (≤ 3.0 × ULN for patients with Gilbert's Syndrome or liver metastases); Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and Alkaline Phosphatase (ALP) ≤ 2.5 × ULN (≤ 5.0 × ULN for patients with documented liver or bone metastases); Serum albumin ≥ 2.8 g/dL.

Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN.

Cardiac: Left Ventricular Ejection Fraction (LVEF) ≥ 50%.

• Anticipated survival time ≥ 16 weeks.
• Agreement to use highly effective contraception methods during the trial and for 12 months after the last dose of treatment.
• Voluntarily participate in the study, sign the Informed Consent Form (ICF), demonstrate good compliance, and be willing to cooperate with follow-up.

Exclusion criteria

• Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents.
• Known hypersensitivity to recombinant humanized anti-PD-1 monoclonal antibodies or any of their components.
• Active skin breakdown, infection, ulceration, necrosis, bleeding at the injection site, or a high risk of hollow organ perforation.
• Known allergy or intolerance to Au-TMP active ingredients, excipients, or similar compounds.
• Presence of known driver mutations (e.g., BRAF V600E/K, c-KIT, NRAS) for which targeted therapies are already approved and available as first-line treatment.
• Ocular (uveal) or mucosal melanoma.
• Receipt of other anti-tumor therapies (including corticosteroids or immunotherapy) or participation in other clinical trials within 4 weeks before treatment initiation; failure to recover from toxicities of prior therapies (except Grade 2 alopecia and Grade 1 neurotoxicity).
• Pregnant or breastfeeding women.
• Positive for Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV). Patients with positive Hepatitis B Surface Antigen (HBsAg) or Hepatitis B Core Antibody (HBcAb) must have a negative Hepatitis B Virus (HBV) DNA test (quantitative detection < 500 IU/mL).
• History of active tuberculosis.
• Active autoimmune disease requiring systemic treatment within the past 2 years (except physiological replacement therapy for thyroid, insulin, or adrenal/pituitary insufficiency).
• Serious uncontrolled concurrent medical conditions, including uncontrolled diabetes, interstitial lung disease, New York Heart Association (NYHA) Class III/IV heart failure, severe cardiac arrhythmias, or recent (within 6 months) myocardial infarction or cerebrovascular accidents.
• Active Central Nervous System (CNS) or leptomeningeal metastases. Patients with treated brain metastases are eligible if they are stable (no progression via Magnetic Resonance Imaging (MRI)) for at least 8 weeks post-treatment and 28 days prior to the first dose, and do not require immunosuppressive doses of corticosteroids (>10 mg/day prednisone equivalent) for at least 2 weeks.
• Receipt of hematopoietic stimulants (e.g., G-CSF, EPO) within 2 weeks prior to treatment.
• Receipt of live vaccines within 4 weeks prior to treatment.
• Major surgery (excluding diagnostic procedures) within 4 weeks prior to treatment.
• History of psychiatric disorders or persistent drug/substance abuse.
• Other malignancies within the past 5 years, except for successfully treated localized cancers such as basal/squamous cell skin cancer or in situ carcinomas (cervix, breast, prostate).
• Any other acute or chronic medical/psychiatric condition or laboratory abnormality that, in the investigator's opinion, increases research-related risk or interferes with the interpretation of study results.
• Any condition that is not in the best interest of the participant.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• West China Hospital, Sichuan University — Chengdu
• West China Hospital, Sichuan University — Chengdu

Publications

• Bonvalot S, Rutkowski PL, Thariat J, Carrere S, Ducassou A, Sunyach MP, Agoston P, Hong A, Mervoyer A, Rastrelli M, Moreno V, Li RK, Tiangco B, Herraez AC, Gronchi A, Mangel L, Sy-Ortin T, Hohenberger P, de Baere T, Le Cesne A, Helfre S, Saada-Bouzid E, Borkowska A, Anghel R, Co A, Gebhart M, Kantor G, Montero A, Loong HH, Verges R, Lapeire L, Dema S, Kacso G, Austen L, Moureau-Zabotto L, Servois PMID 31296491
• Zhang Y, Huang F, Ren C, Liu J, Yang L, Chen S, Chang J, Yang C, Wang W, Zhang C, Liu Q, Liang XJ, Liu J. Enhanced Radiosensitization by Gold Nanoparticles with Acid-Triggered Aggregation in Cancer Radiotherapy. Adv Sci (Weinh). 2019 Jan 8;6(8):1801806. doi: 10.1002/advs.201801806. eCollection 2019 Apr 17. PMID 31016110
• Jiang Y, Cao H, Deng H, Guan L, Langthasa J, Colburg DRC, Melemenidis S, Cotton RM, Aleman J, Wang XJ, Graves EE, Kalbasi A, Pu K, Rao J, Le QT. Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors. Nat Biotechnol. 2025 Sep;43(9):1496-1509. doi: 10.1038/s41587-024-02448-0. Epub 2024 Oct 24. PMID 39448881
• Gorodetska I, Schulz A, Behre G, Dubrovska A. Confronting Melanoma Radioresistance: Mechanisms and Therapeutic Strategies. Cancers (Basel). 2025 Aug 14;17(16):2648. doi: 10.3390/cancers17162648. PMID 40867277
• Zhao Y, Zhang T, Wang Y, Lu D, Du J, Feng X, Zhou H, Liu N, Zhu H, Qin S, Liu C, Gao X, Yang Z, Liu Z. ICAM-1 orchestrates the abscopal effect of tumor radiotherapy. Proc Natl Acad Sci U S A. 2021 Apr 6;118(14):e2010333118. doi: 10.1073/pnas.2010333118. PMID 33785590
• Sheng X, Huang G, Fang M, Li K, Wu D, Zhang X, Chen J, Zhu D, Chen Y, Li H, Gao Q, Wu L, Tang B, Yan X, Zeng R, Li J, Yu W, Xu J, Hao Y, Jin C, Zou J, Guo J. Toripalimab vs Dacarbazine as First-Line Therapy for Advanced Melanoma of Acral Subtype: The Phase 3 MELATORCH Randomized Clinical Trial. JAMA Oncol. 2026 Mar 1;12(3):243-250. doi: 10.1001/jamaoncol.2025.5751. PMID 41481311
• Jalil A, Donate MM, Mattei J. Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma. Cancer Drug Resist. 2024 Oct 31;7:42. doi: 10.20517/cdr.2024.54. eCollection 2024. PMID 39534873
• Seth R, Agarwala SS, Messersmith H, Alluri KC, Ascierto PA, Atkins MB, Bollin K, Chacon M, Davis N, Faries MB, Funchain P, Gold JS, Guild S, Gyorki DE, Kaur V, Khushalani NI, Kirkwood JM, McQuade JL, Meyers MO, Provenzano A, Robert C, Santinami M, Sehdev A, Sondak VK, Spurrier G, Swami U, Truong TG, Tsai KK, van Akkooi A, Weber J. Systemic Therapy for Melanoma: ASCO Guideline Update. J Clin Oncol. PMID 37579248

Identifiers

NCT: NCT07562841 · 2026-811

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗