A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Manganese-primed Immunochemotherapy in Subjects With Advanced Ovarian Cancer
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 120
- 试验地点
- 6
- 主要终点
- Progression-free survival (PFS)
研究概览
简要总结
Epithelial ovarian cancer is the most lethal gynecologic malignancy, and most patients eventually relapse and develop resistance to available therapies. Immune checkpoint inhibitors have shown limited overall efficacy in recurrent ovarian cancer, partly because of its immunosuppressive tumor microenvironment. Manganese (Mn2+) can activate the cGAS-STING pathway and may enhance antitumor immunity and the therapeutic effects of PD-1 blockade combined with chemotherapy. Following encouraging findings from an early-phase study, a randomized, single-blind, placebo-controlled phase II trial showed that the addition of manganese chloride to anti-PD-1 antibody, nab-paclitaxel, and cisplatin improved clinical outcomes compared with placebo, with an overall manageable safety profile. Based on these findings, this phase III trial is designed to confirm the efficacy and further evaluate the safety of Mn2+-primed immunochemotherapy in patients with advanced ovarian cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patients with histologically or cytologically confirmed epithelial ovarian cancer, primary fallopian tube cancer, or peritoneal cancer.
- •Patients who have received at least two prior lines of systemic therapy, including at least one platinum-based regimen.
- •Patients who experienced disease progression during or within 6 months after completion of the most recent line of systemic therapy.
- •Note: This most recent therapy is not required to be platinum-based and may be any systemic treatment (chemotherapy, targeted therapy, or other anticancer therapy).
- •Patients with at least one measurable lesion.
- •Patients who have received immunotherapy (anti-PD-1 antibodies, anti-PD-L1 antibodies), or bevacizumab, are not restricted from enrollment.
- •Expected survival of more than 6 months.
- •Age over 18 years.
- •Patient weight > 40 kg.
- •ECOG performance status ≤
- •Peripheral blood white blood cell count > 3.5×10 /L.
- •Bone marrow reserve and liver and kidney function (the following laboratory tests should be performed before initial treatment to prove):
- •Absolute neutrophil count (ANC) ≥ 1,000/mm ;
- •Hemoglobin > 80 g/dL;
- •Platelet count > 80,000/mm ;
- •ALT/AST < 3×ULN;
- •Serum creatinine < 3×ULN;
- •Total bilirubin level < 3×ULN.
- •No significant hereditary diseases.
- •Normal liver and kidney biochemical indicators.
- •Completed the last systemic anticancer therapy at least 4 weeks prior to enrollment, with resolution of all treatment-related adverse events to grade ≤1 according to NCI-CTCAE v5.0, with the exception of alopecia and other clinically insignificant toxicities deemed acceptable by the investigator.
- •No treatment with paclitaxel (albumin-bound) plus platinum in the past 3 months.
- •Voluntary participation and signing of informed consent, compliance with the trial treatment plan and visit schedule, and cooperation in observing adverse events and efficacy.
排除标准
- •Absolute neutrophil count (ANC) < 1×10 /L or platelets < 80×10 /L or hemoglobin < 80 g/dL (according to the normal values of the clinical trial center）.
- •Serum total bilirubin levels higher than 3 times the upper limit of the reference range.
- •ALT, AST, or ALP levels higher than 3 times the upper limit of the reference range when there are no liver metastases; ALT, AST, or ALP levels higher than 5 times the upper limit of the reference range when there are liver metastases.
- •Patients receiving known strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin or St. John's Wort) of CYP3A4, or strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C8; patients receiving treatment with potent P-gp inhibitors or inducers, or patients who cannot stop treatment with these agents for 2 weeks before the start of the study.
- •Subjects' bowel obstruction or requirement for bowel obstruction-related interventions within 3 weeks prior to first study drug administration; subjects with incomplete bowel obstruction who have returned to normal within 1 month before the first dose of the experimental drug can be included in the study after discussion by the researchers.
- •Patients with severe or uncontrolled ascites, defined as either of the following: a) symptomatic ascites corresponding to CTCAE ≥ Grade 2; b) history of therapeutic paracentesis for ascites within 3 weeks prior to enrollment.
- •Organ failure:
- •Heart: Grade III or IV.
- •Liver: Grade C according to Child-Pugh B liver function classification.
- •Kidney: Renal failure and uremia.
- •Lung: Severe respiratory failure symptoms.
- •Brain: Consciousness disorders.
- •T-cell tumors such as T-cell lymphoma or T-cell leukemia.
- •Major surgery within 4 weeks before enrollment, or planned major surgery during the study (excluding diagnostic surgery).
- •HIV antibody positive, or other acquired, congenital immunodeficiency diseases, or patients with a history of organ transplantation.
- •History of Parkinson's disease or epilepsy, or occurrence of diseases that can induce seizures within 12 months before the study (including a history of transient ischemic attack, stroke, traumatic brain injury with consciousness disorders).
- •CTCAE grade 2 infections that do not respond to treatment or active clinically serious infections with CTCAE > Grade
- •Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment.
- •Patients with a history of allergic reactions to study drug components or suspected allergies.
- •Chronic diseases requiring immunotherapy or hormone therapy.
- •Patients who have received any investigational drug treatment within 30 days before the first dose of the trial drug.
- •Subjects with symptoms of brain or leptomeningeal metastasis.
- •Subjects with a history of malignant tumors (non-study tumor) within 3 years before the first dose of the trial drug.
- •History of the following diseases: interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic diseases including diabetes, hypertension, pulmonary fibrosis, acute lung disease, abdominal infection, etc.
研究组 & 干预措施
Manganese primed anti-PD-1 plus nPP chemotherapy
Subject received Manganese primed anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Anti-PD-1 antibody (Drug)
anti-PD-1 plus nPP chemotherapy
Subject received placebo, anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Anti-PD-1 antibody (Drug)
anti-PD-1 plus nPP chemotherapy
Subject received placebo, anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Placebo (Drug)
anti-PD-1 plus nPP chemotherapy
Subject received placebo, anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Nab-paclitaxel (Drug)
anti-PD-1 plus nPP chemotherapy
Subject received placebo, anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Platinum chemotherapy (Drug)
Manganese primed anti-PD-1 plus nPP chemotherapy
Subject received Manganese primed anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Nab-paclitaxel (Drug)
Manganese primed anti-PD-1 plus nPP chemotherapy
Subject received Manganese primed anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Manganese Chloride (Drug)
Manganese primed anti-PD-1 plus nPP chemotherapy
Subject received Manganese primed anti-PD-1 antibody, nab-paclitaxel and platinum chemotherapy every 3 weeks until achieving a second assessable complete response or progressive disease, development of unacceptable toxicity, or withdrawal of consent.
干预措施: Platinum chemotherapy (Drug)
结局指标
主要结局
Progression-free survival (PFS)
时间窗: 12 months
PFS time was measured from study entry to the first documentation of disease progression or death. Disease progression was determined per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
次要结局
- Overall survival (OS)(24 months)
- Object response rate (ORR)(24 months)
- Number of Subjects with treatment-related adverse events (AEs)(12 months)
研究者
Han weidong
Principal Investigator
Chinese PLA General Hospital