A Phase I Study to Evaluate the Safety, Tolerability, PK/PD and Immunogenicity Characteristics of Recombinant Anti-CD38 and Anti-CD3 Bispecific Antibodies (Y150) for Injection in Patients With Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Number of Participants With Adverse Events according to CTCAE V5.0
研究概览
简要总结
The main purpose of this Phase I study is to access the safety and tolerability of Y150 at different dose levels. It is hoped to find out the recommended dose for Phase II/III.
详细描述
This is a Phase I, open-label，dose-escalation trial in patients with relapsed or refractory multiple myeloma. There are two parts of the study: a dose-escalation part and a dose-expansion part. Dose escalation follows an accelerated design initially with 2 single subject cohorts (Cohorts 1-2) and switches to a classical 3+3 design (Cohorts 3-7). Dose-expansion means that at least 9 subjects (included subjects of the dose-escalation part) will be selected in 1 - 3 dose levels to focus on the pharmacokinetics (PK) / pharmacodynamic (PD) features and recommended dose for Phase II (RP2D). Additional purpose of the study is to find out whether the study drug has anti-tumor effects.
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
- •Male or female ≥ 18 years.
- •Subject has a history of multiple myeloma with relapsed and refractory disease, and must have received at least 2 prior multiple myeloma treatment regimens (including a proteasome inhibitor and an immunomodulatory agent), or can not tolerate the toxicity of PIs and IMIDS; or have drug resistance to one and toxic intolerance to the other.
- •Relapsed multiple myeloma is defined as IMWG criteria in 2016, including clinical relapse or relapse after CR.
- •Refractory multiple myeloma is defined as failure of initial or salvage therapy to achieve at least a minimal response (only achieve SD after treatment ≥ 2 cycles ), or disease progression during treatment or within 60 days after the last treatment.
- •Subjects must have measurable disease, including at least one of the criteria below:
- •M-protein ≥ 10 g/L by SPEP/immunofixation for subjects with immunoglobulin class G (IgG) myeloma , M-protein ≥ 5g/L for subjects with IgA, IgD, IgE, IgM myeloma or
- •≥ 200 mg/24 hours urine collection by UPEP or
- •Serum free light chain (FLC) levels ≥ 100 mg/L and an abnormal kappa/lambda (κ/λ) ratio in patients without detectable serum or urine M-protein
- •The interval between the last anti-tumor treatment and the first administration of Y150 (including PIS and IMADs) ≥4 weeks, the interval between CD38 mAb administration and the first administration of Y150 ≥12 weeks;
- •ECOG performance status 0 - 2;
- •Life expectancy ≥ 3 months
- •Adequate hematological function as evidenced by meeting all the following requirements:
- •Absolute neutrophil count ≥1.0×109/L (growth factor support not allowed within 48h)
- •Hemoglobin > 70 g/L( without blood transfusion within 7 days)
- •Platelet count ≥50×109/L(without transfusion within 7 days)
- •Adequate hepatic function as evidenced by meeting all the following requirements:
- •Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
- •Aspartate aminotransferase (AST), and alanine aminotransferase (ALT)≤ 2.5 × ULN;
- •Calculated creatinine clearance (CrCL) ≥ 30 mL/min
- •Understand and voluntarily sign written informed consent.
排除标准
- •Subject has central nervous system involvement of multiple myeloma.
- •Subject has received ≥ 10 mg/day prednisone equivalent within one week before starting Y
- •Subject with primary or secondary plasma cell leukemia.
- •Subject had a prior autologous stem cell transplant ≤ 12 weeks months prior to starting Y150, or had a prior autologous stem cell transplant history.
- •Subject received a chimeric antigen receptor T (CAR T) cell product ≤ 6 months prior to starting Y
- •Concurrent malignancy within 5 years prior to entry other than adequately treated cervical carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma, prostate cancer under active surveillance, prostate cancer that has undergone definitive treatment, ductal carcinoma in situ of the breast, or ≤ T1 urothelial carcinoma.
- •Allergy to Abs drugs or human protein.
- •Active infection(CTCAE Grade ≥2).
- •Subjects with severe respiratory disease, and to be unsuitable to participate in study by investigators judgment.
- •Severe cardiovascular disease, including a history of CABG or PCI, myocardial infarction within 6 months of study entry, unstable angina ,NYHA class III or IV heart failure, uncontrolled hypertension or left ventricular ejection fraction <50%
- •QTc interval > 480 ms; Family or personal with a history of long or short QT syndrome; significant clinical history of ventricular arrhythmias, or currently receiving antiarrhythmic drugs or implanted defibrillator to treat ventricular arrhythmias.
- •Patients with a history of active autoimmune diseases (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis etc.), except when the disease is in a stable state (without systemic immunosuppressant treatment, the symptoms are stable for more than 6 months).
- •Patients with severe hyperthyroidism or hypothyroidism.
- •Patients with metabolic diseases such as uncontrolled diabetes, severe gastrointestinal bleeding, severe diarrhea (Grade ≥ 2 according to CTCAE), or severe gastrointestinal obstruction requiring intervention.
- •Patients with a history of immunodeficiency, including HIV positive.
- •HIV antibody, TP antibody and HCV antibody were positive, HBsAg positive and hepatitis B virus DNA test showed that patients with active hepatitis B (HBV-DNA ≥ 1000cps/ml).
- •Patients who have received inoculation of (attenuated) live virus vaccine within 4 weeks before the first administration.
- •Pregnant, lactating women, or females or males who have fertility plan within 6 months during the study and after the end of the medication.
- •Patients with a previous history of definite neurological or psychiatric disorders, and investigator believe that it affects patients' cognitive function or compliance, including unstable epilepsy, dementia, schizophrenia, etc.
- •Any condition that the investigator believes may not be appropriate for participating the study.
研究组 & 干预措施
Y150
Subjects who meet the enrollment criteria will enter the core treatment period and receive a cycle of treatment with Y150 (once weekly for 4 weeks) via intravenous infusion. And eligible subjects 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: Y150 (Drug)
结局指标
主要结局
Number of Participants With Adverse Events according to CTCAE V5.0
时间窗: up to approximately 2 years
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: From the time of first dosing (Day 1) until the forth dosing (Day 28)
DLTs were assessed using the national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 5.0.
次要结局
- Half-time (t1/2) of Y150(Up to 1 weeks after the fourth dosing.)
- Area under the curve (AUC) of Y150(Up to 1 weeks after the fourth dosing.)
- Peak Plasma Concentration (Cmax) of Y150(Up to 1 weeks after the fourth dosing.)
- Anti-drug antibodies(ADAs) titer(12 months (anticipated))
- neutralizing antibody titer(12 months (anticipated))
- Duration of Response(12 months (anticipated))
- lymphocyte subsets in peripheral blood(12 months (anticipated))
- Cytokines levels in serum(12 months (anticipated))
- Objective Response Rate (ORR)(12 months (anticipated))
- Time to Progression (TTP)(12 months (anticipated))
- Progression-Free Survival (PFS)(12 months (anticipated))
- Overall Survival (OS)(12 months (anticipated))
- Time to first Response(12 months (anticipated))