Enhancing Immunogenicity in NRAS-Mutant Melanoma Via Autophagy Modulation: A Clinical and Mechanistic Study.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
This study evaluates the combination of the autophagy inhibitor hydroxychloroquine (HCQ), the MEK inhibitor tunlametinib, and the anti-PD-1 antibody pucotenlimab in patients with locally advanced or metastatic melanoma. The primary objectives are to assess the objective response rate (ORR) and progression-free survival (PFS). Secondary objectives include evaluating adverse events (type, severity, and incidence), duration of response (DOR), disease control rate (DCR), and overall survival (OS), as well as exploring the molecular mechanisms by which autophagy modulation enhances immunogenicity in mutant melanoma. Further exploratory analyses will examine the mechanisms by which autophagy inhibition enhances tumor sensitivity to PD-1 blockade, thereby establishing experimental and theoretical grounds for refining future clinical approaches.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years of age, both genders.
- •Subjects with unresectable or metastatic melanoma (Stage III/IV) confirmed by histology or cytology
- •The mutated NRAS genes were confirmed by sequencing.
- •Prior systemic antineoplastic therapy is allowed. All acute toxic effects of prior antitumor therapy must have resolved to grade 1 or lower before the start of the study drug, with the exception of alopecia (grade 1 or 2 permitted), neurotoxicity (grade 1 or 2 permitted), or bone marrow parameters (grade 1, 2, or 3 permitted).
- •The life expectance should be at least 12 months.
- •Eligible subjects had not received chemotherapy for locally advanced or metastatic disease and had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria).
- •To ensure eligibility, the following criteria must be met regarding major organ and bone marrow functions: Adequate bone marrow function: absolute neutrophil count (ANC)≥ 1.5^109/L, platelet count (PLT)≥ 100^109/L, and hemoglobin level (HB)≥ 9 g/dL (no transfusion received within 14 days). Serum total bilirubin (TBIL) must be ≤ 1.5 times the upper limit of normal (ULN). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times the upper limits of normal, serum creatinine ≤1.5, and Creatinine clearance had to be greater than 50 mL/min. Creatinine clearance, as an estimate of glomerular filtration rate (eGFR), was calculated according to the Cockcroft and Gault (C&G) equation (26): (140 - age [years] × weight [kg] × 0.85 for male)/ 72*serum creatinine (μmol/L). The International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) were a maximum of 1.5 fold the upper limit of normal (This provision applies only to Subjects not receiving anticoagulant therapy; for Subjects receiving anticoagulant therapy, anticoagulation should be within the therapeutic range.). Urine protein ≤ 1+; if urine protein > 1+, a 24-hour urine collection for protein quantification is required, and the total protein must be ≤ 1 g; FT3, FT4, and TSH levels should be normal, or any abnormalities should be clinically insignificant; lactate dehydrogenase (LDH) ≤ 2 × upper limit of normal (ULN).
- •A urine pregnancy test must be negative within 7 days before enrollment for women of childbearing potential.Male and female Subjects of reproductive/childbearing potential must use highly effective contraception (e.g., oral contraceptives, IUDs, abstinence, or barrier plus spermicide) during the entire trial and for 12 months after treatment ends.
- •The subject voluntarily joins the study, has good compliance, and is cooperative with follow-up evaluations.
排除标准
- •Subjects who have previously received anti-PD-1 antibody, anti-PD-L1/PD-L2 antibody therapy, and/or VEGFR TKI therapy.
- •Subjects currently receiving systemic anti-tumor therapy.
- •Subjects who have participated in or are currently participating in other drug/therapy clinical trials within 4 weeks prior to enrollment (calculated from the date of the last dose of the previous trial).
- •Subjects who have undergone major surgery within 4 weeks prior to enrollment, or have not recovered from surgical side effects, or have received live vaccination within 4 weeks prior to enrollment.
- •Subjects with a history of other invasive malignancy within the previous 5 years other than nonmelanoma skin cancer were excluded, except for curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early-stage prostate cancer, and cervical carcinoma in situ.
- •Subjects who have received hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), erythropoietin, etc., within 1 week prior to enrollment.
- •Subjects with positive test results for HIV antibody or Treponema pallidum antibody (based on test results from a Grade A tertiary hospital, including the study center).
- •Subjects with active hepatitis B or hepatitis C who have not received antiviral therapy: if HBsAg or HBcAb is positive, HBVDNA should be tested (with results above the upper limit of normal range at the research center); if HCV antibody is positive, HCVRNA should be tested (with results above the upper limit of normal range at the research center).
- •Subjects with known allergy to humanized anti-PD-1 monoclonal antibody drugs and their components; known allergy to MEK inhibitors (e.g., Tunlametinib) and any of their excipients; known allergy to autophagy inhibitors (e.g., hydroxychloroquine) and any of their excipients.
研究组 & 干预措施
Tunlametinib + Pucotenlimab + Hydroxychloroquine
PD-1 antibody (pucotenlimab):
Administered via intravenous infusion over at least 60 minutes, using an in-line filter (0.2-5 μm). The drug is diluted with normal saline prior to infusion. One treatment cycle is defined as 3 weeks (21 days).
Tunlametinib (3 mg/tablet):
The recommended dose is 12 mg (4 tablets) orally twice daily (approximately every 12 hours), with or without food. Capsules must not be chewed, dissolved, or opened. If a dose is missed, it may be taken up to 8 hours before the next scheduled dose; if the missed dose is discovered within 8 hours of the next dose, it should be skipped.
Hydroxychloroquine (0.1 g/tablet):
Administered orally at 2 tablets (0.2 g) twice daily, to be taken with meals or milk. Each treatment course consists of 4 consecutive weeks of administration, i.e., 30 days per course.
Treatment discontinuation criteria:
Patients were permitted to continue treatment until disease progression or development of unacceptable toxicity.
干预措施: Pucotenlimab (Drug)
Tunlametinib + Pucotenlimab + Hydroxychloroquine
PD-1 antibody (pucotenlimab):
Administered via intravenous infusion over at least 60 minutes, using an in-line filter (0.2-5 μm). The drug is diluted with normal saline prior to infusion. One treatment cycle is defined as 3 weeks (21 days).
Tunlametinib (3 mg/tablet):
The recommended dose is 12 mg (4 tablets) orally twice daily (approximately every 12 hours), with or without food. Capsules must not be chewed, dissolved, or opened. If a dose is missed, it may be taken up to 8 hours before the next scheduled dose; if the missed dose is discovered within 8 hours of the next dose, it should be skipped.
Hydroxychloroquine (0.1 g/tablet):
Administered orally at 2 tablets (0.2 g) twice daily, to be taken with meals or milk. Each treatment course consists of 4 consecutive weeks of administration, i.e., 30 days per course.
Treatment discontinuation criteria:
Patients were permitted to continue treatment until disease progression or development of unacceptable toxicity.
干预措施: Tunlametinib (Drug)
Tunlametinib + Pucotenlimab + Hydroxychloroquine
PD-1 antibody (pucotenlimab):
Administered via intravenous infusion over at least 60 minutes, using an in-line filter (0.2-5 μm). The drug is diluted with normal saline prior to infusion. One treatment cycle is defined as 3 weeks (21 days).
Tunlametinib (3 mg/tablet):
The recommended dose is 12 mg (4 tablets) orally twice daily (approximately every 12 hours), with or without food. Capsules must not be chewed, dissolved, or opened. If a dose is missed, it may be taken up to 8 hours before the next scheduled dose; if the missed dose is discovered within 8 hours of the next dose, it should be skipped.
Hydroxychloroquine (0.1 g/tablet):
Administered orally at 2 tablets (0.2 g) twice daily, to be taken with meals or milk. Each treatment course consists of 4 consecutive weeks of administration, i.e., 30 days per course.
Treatment discontinuation criteria:
Patients were permitted to continue treatment until disease progression or development of unacceptable toxicity.
干预措施: Hydroxychloroquine (HC) (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: up to 180 days
Defined as the percentage of subjects achieving complete response (CR) or partial response (PR) as assessed by RECIST 1.1.
Progression Free Survival (PFS)
时间窗: up to 180 days
Defined as the time from randomization to the date of first documentation of from date of randomization until the date of first documented progression or date of death from any cause, whichever came first.
次要结局
- Disease Control Rate (DCR)(up to 180 days)
- Duration of Response (DoR)(up to 180 days)
- Incidence and severity of adverse events (AEs)(30 Days, an average of 3 months)
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(30 days (average of 3 months).)
研究者
Rongcheng Zhang
M.D.
Sun Yat-sen University