A Phase 1, Multicenter, Open-label, Dose-escalation Study to Evaluate the Safety, Tolerability and PK/PD of Recombinant Anti-EpCAM and Anti-CD3 Human-Mouse Chimeric Bispecific Antibody Via Intraperitoneal Infusion in Malignant Ascites
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 2
- 主要终点
- Incidence of AEs
研究概览
简要总结
This study is to investigate the safety, tolerability, PK, PD and immunogenicity of multiple ascending doses of M701 administered intraperitoneally to patients with malignant ascites caused by advanced solid tumors.
详细描述
To evaluate the safety and tolerability of multiple ascending doses of M701 administered intraperitoneally in patients with malignant ascites.
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
- •Males or females, aged > 18 years;
- •Histologically- or cytologically-confirmed advanced solid tumors;
- •Patients who require therapeutic paracentesis, defined as at least 1 therapeutic paracentesis (e.g., to relieve abdominal pressure and discomfort) during 4 weeks prior to the baseline paracentesis;
- •Patients who have failed to standard treatment, or who have no standard treatment available that may confer clinical benefit;
- •EpCAM+ tumor cells in ascites fluid;
- •Patients who have received anti-tumor therapy including chemotherapy, hormone therapy, radiotherapy (except local radiotherapy for pain relief) ≥ 2 weeks or received immunotherapy, biological agents ≥ 3 weeks prior to the first dose of study drug;
- •Patients who have recovered from any toxic reaction to previous medications (Grade 0 or 1 based on NCI-CTCAE v5.0);
- •Patients with an ECOG Performance Status score (PS) 0-3;
- •Patients with a life expectancy > 8 weeks;
- •Organ function levels must meet the following requirements:
- •Bone marrow: absolute neutrophil count (ANC) ≥ 1.5 ×10^9/L, platelet count ≥ 80 ×10^9/L, hemoglobin ≥ 9.0 g/dL (without blood transfusion within14 days of the first dose of study drug); Liver: bilirubin ≤ 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3 x ULN ( ≤ 5 x ULN in case of liver metastases); Kidney: serum creatinine ≤1.5 x ULN and estimated glomerular filtration rate (eGFR) ≥ 50 ml/min;
- •Patients must understand and voluntarily sign the informed consent form.
排除标准
- •Known to have a history of allergy to the active ingredients of M701; or with a definite history of drug allergy or specific allergy (asthma, rubella, eczema dermatitis);
- •Known or suspected hypersensitivity to M701 or similar antibodies;
- •Extensive liver metastases (> 70% organ volume comprises malignancy);
- •Uncontrolled active infection (CTCAE ≥ Grade 2);
- •Serious diarrhea (CTCAE ≥ Grade 2);
- •Serious dyspnea requiring oxygen therapy;
- •History of auto-immune diseases (e.g. inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, serious psoriasis, rheumatoid arthritis);
- •History of acute or chronic pancreatitis;
- •Other serious diseases that may prevent patients participation in this trial (such as uncontrolled diabetes mellitus, severe gastrointestinal disorders);
- •Cardiac insufficiency, NYHA class III or IV;
- •Intestinal obstruction that occurred within 30 days prior to the first dose of study drug;
- •Non-drainable ascites;
- •Confirmed portal vein obstruction;
- •History of immunodeficiency, including positive HIV test;
- •Active hepatitis B virus infection or hepatitis C virus infection, positive syphilis antibody test and positive HIV antibody test;
- •Pregnant or breastfeeding woman;
- •Plan to conceive within six months;
- •Previous confirmed history of neurological or mental disorders, including epilepsy and dementia;
- •Have received a clinical study active drug treatment within 1 month prior to the first dose of study drug;
- •Those that are deemed ineligible for this clinical trial by study personnel.
研究组 & 干预措施
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 4 of M701 (Drug)
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 1 of M701 (Drug)
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 2 of M701 (Drug)
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 3 of M701 (Drug)
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 5 of M701 (Drug)
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 6 of M701 (Drug)
M701
Patients will undergo a 2-week screening period and a 4-week core treatment period, and eligible patients who complete the core treatment period will receive a cycle of extended treatment (once weekly for 4 weeks) until disease progression or toxicity intolerance.
干预措施: Cohort 7 of M701 (Drug)
结局指标
主要结局
Incidence of AEs
时间窗: From the start of administration to the end of the study or 28 days after the administration is stopped (up to 6 months and 28 days)
Incidence and severity of AEs, including but not limited to vital signs, physical examination, laboratory tests. All AEs will be classified as Grades 1 through 5 as defined by NCI CTCAE v5.0.
MTD
时间窗: From the time of the first dose (Day 1) until the forth dosing (Day 28)
Number of DLTs (dose limiting toxicities) during the first 28 days after the first administrations of study drug in each cohort.
次要结局
- Cytokines(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Maximum observed concentration (Cmax) of M701(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Minimum observed concentration (Cmin) of M701(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Number of subjects who develop detectable anti-drug antibodies (ADAs)(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Expression levels of CA19-9(From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).)
- Expression levels of AFP(From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).)
- Area under the curve (AUC) of M701(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- The antibody titer of the neutralizing antibody(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Expression levels of CEA(From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).)
- Counts of Lymphocyte subsets(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Ascites volume(From the time of first dosing (Day 1) until disease progression or toxicity intolerance (up to 6 months).)
- Expression levels of CA125(From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).)
- Expression levels of CA72-4(From the time of screening period until disease progression or toxicity intolerance (up to 6 months and 14 days).)