Neoadjuvant Pucotenlimab Combined With Lenvatinib and Temozolomide in Resectable Stage IIB/III Acral Melanoma

A Single-Arm, Single-Center, Phase II Exploratory Study of Neoadjuvant Pucotenlimab Combined With Lenvatinib and Temozolomide in Resectable Stage IIB/III Acral Melanoma（TRIUMPH-AM）

This is a single-arm, open-label, single-center, Phase II exploratory clinical study evaluating the efficacy, safety, and tolerability of neoadjuvant pucotenlimab combined with lenvatinib and temozolomide in patients with resectable Stage IIB/III acral melanoma.

After providing written informed consent, eligible subjects will receive neoadjuvant combination therapy consisting of pucotenlimab, lenvatinib, and temozolomide, with each treatment cycle lasting 3 weeks. Surgical resection will be performed after 3 cycles of treatment. Postoperative adjuvant therapy will be determined based on the pathological results of the surgical specimens. Subjects who do not achieve a major pathological response (MPR) will receive pucotenlimab maintenance therapy for a total of 1 year, while subjects who achieve an MPR will be exempt from adjuvant therapy.

Treatment will continue until the completion of adjuvant therapy, disease progression, unacceptable toxicity, initiation of a new anti-tumor therapy, withdrawal of informed consent, loss to follow-up, death, or discontinuation determined by the investigator, whichever occurs first.

Inclusion Criteria:

• Fully understand the study and voluntarily sign the informed consent form (ICF). (Note: Items 1 and 10 are similar, but both are translated here) Age ≥ 18 and ≤ 75 years old. Histologically or cytologically confirmed resectable Stage IIB-III melanoma. Have at least one measurable lesion according to RECIST 1.1 criteria. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.

Life expectancy of ≥ 6 months. No prior systemic drug therapy for melanoma.

Adequate major organ function meeting the following criteria:

Hematology (without blood transfusion or use of hematopoietic stimulating factors within 14 days): Hemoglobin (Hb) ≥ 90 g/L; Absolute Neutrophil Count (ANC) ≥ 1.5×10^9/L; Platelets (PLT) ≥ 100×10^9/L; White Blood Cell (WBC) count ≥ 3.0×10^9/L.

Biochemistry: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (upper limit of normal) (for patients with liver metastasis, ≤ 5 × ULN); Serum total bilirubin (TBIL) ≤ 1.5 × ULN (for patients with Gilbert's syndrome, ≤ 3 × ULN); Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance rate ≥ 50 ml/min.

Coagulation: Activated partial thromboplastin time (APTT), International Normalized Ratio (INR), and Prothrombin Time (PT) ≤ 1.5 × ULN.

Doppler ultrasound assessment: Left ventricular ejection fraction (LVEF) ≥ 50%. Women of childbearing potential must agree to use acceptable methods of contraception (e.g., intrauterine device [IUD], oral contraceptives, or condoms) during the study and for 6 months after the end of the study; must have a negative serum pregnancy test within 7 days prior to study enrollment, and must not be breastfeeding. Male patients must agree to use acceptable methods of contraception during the study and for 6 months after the end of the study.

Agree to and sign the study Informed Consent Form (ICF) before initiating any study-related procedures.

Exclusion Criteria:

• Prior treatment with immune checkpoint inhibitors (including but not limited to pembrolizumab, nivolumab) or lenvatinib.

Received anti-cancer therapy within 28 days (or 5 times the half-life, whichever is shorter) prior to the first dose of study treatment, or received any investigational drug therapy within 30 days.

Underwent major surgery, open biopsy, or experienced major trauma within 4 weeks prior to enrollment.

Use of immunosuppressive medications within 14 days prior to the start of treatment, excluding intranasal and inhaled corticosteroids or physiological doses of systemic corticosteroids (i.e., daily dose of prednisolone ≤ 10 mg or equivalent physiological doses of other corticosteroids).

Any active autoimmune disease or a history of autoimmune disease (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism; except for subjects with vitiligo or asthma that completely resolved in childhood and currently do not require medical intervention, or a history of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant).

INR > 1.5 or APTT > 1.5 × ULN. Currently poorly controlled hypertension, defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg.

Subjects with proteinuria > 1+ on urinalysis will undergo a 24-hour urine collection to quantitatively assess proteinuria; those with urine protein ≥ 1 g/24 hours will be ineligible.

Any current disease or condition that affects drug absorption, or inability to take lenvatinib orally.

Current digestive tract diseases such as active gastric/duodenal ulcers or ulcerative colitis, active bleeding from an unresected tumor, or other conditions judged by the investigator as likely to cause gastrointestinal bleeding or perforation.

Evidence or history of significant bleeding tendency within 3 months prior to enrollment (bleeding > 30 mL within 3 months, hematemesis, melena, hematochezia), hemoptysis (> 5 mL of fresh blood within 4 weeks), or occurrence of thromboembolic events (including stroke and/or transient ischemic attack) within 12 months.

Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months prior to enrollment; New York Heart Association (NYHA) Class > 2 congestive heart failure; ventricular arrhythmias requiring medical treatment; LVEF < 50%.

History of other malignancies within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.

Active or poorly controlled severe infections (≥ CTCAE v5.0 Grade 2 infection). Known human immunodeficiency virus (HIV) infection; known history of clinically significant liver disease, including viral hepatitis [known hepatitis B virus (HBV) carriers must rule out active HBV infection, i.e., HBV DNA positive (> 1×10^4 copies/mL or > 2000 IU/mL); known hepatitis C virus (HCV) infection with positive HCV RNA (> 1×10^3 copies/mL), or other hepatitis, cirrhosis] (excluding patients whose relevant test results returned to normal after prior antiviral treatment).

Unstable or clinically symptomatic brain metastases. Persistent toxicities from any prior anti-tumor therapies that have not recovered to ≤ CTCAE v5.0 Grade 2, though patients with any grade of alopecia are permitted to participate.

Pregnant (positive pregnancy test prior to administration) or breastfeeding women.

Received brachytherapy (radioactive seed implantation) within 60 days prior to enrollment.

Any other disease, clinically significant metabolic abnormality, physical examination abnormality, or laboratory abnormality that, in the investigator's judgment, gives reasonable suspicion that the patient has a disease or condition unsuitable for the use of the study drug (e.g., seizures requiring treatment), or that would affect the interpretation of study results or place the patient at high risk.