A Phase I/II Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Mitoxantrone Hydrochloride Liposome Injection in Subjects With Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- DLT
研究概览
简要总结
This is a multi-center, open-label, single-arm, phase I/II study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of mitoxantrone hydrochloride liposome injection in subjects with acute myeloid leukemia (AML).
详细描述
This study will have two stages. Stage 1: Dose escalation, about 9-18 subjects, who are either refractory to induction therapy or have relapsed (R/R) after achieving remission with prior therapy will be recruited. The enrolled subjects will receive Mitoxantrone Hydrochloride Liposome injection in one of three dose-escalation (30 mg/m^2, 36 mg/m^2, 40 mg/m^2) by intravenous infusion (IV), every 28 days (q4w, 1 cycle). If the patient achieves remission (at least PR) after at most 2 cycles of induction, the original regimen of consolidation therapy can be continued for 2-4 cycles, with a total course of no more than 6 cycles. The DLT observation period is 28 days after the first dose in cycle 1, and including the first 28 days treatment cycle. Subjects in Cycle 1 will have PK sampling performed. Stage 2: Dose expansion, about 35-72 subjects with R/R AML or unfit AML will be recruited. The subjects will receive Mitoxantrone Hydrochloride Liposome dose according to the results of stage 1. If the patient achieves remission (at least PR) after at most 2 cycles of induction, the original regimen of consolidation therapy can be continued for 2-4 cycles, with a total course of no more than 6 cycles.
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
- •Subjects fully understand, voluntarily participate in this study and sign the informed consent form;
- •Age ≥18 years old, male or female;
- •Morphological and/or pathological confirmation of relapsed/refractory AML after prior anti-leukemic therapy or newly diagnosed unfit AML (dose expansion stage) , which are judged by the investigator to be unsuitable for intensive chemotherapy;
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 for subjects with R/R AML or aged over 75 years old, 0-3 for subjects with unfit AML aged 18 to 74 years old;
- •The organ function level must meet the following requirements:
- •Liver function : Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times normal upper limit (ULN); Total bilirubin ≤1.5 x ULN ( ≤ 3.0 x ULN for subjects with unfit AML); Renal function: Blood creatinine ≤1.5 x ULN (creatinine clearance <45 mL/min for subjects with unfit AML);
- •Subjects and their partners agree to take effective contraception from the date of signing an informed consent to 6 months after the last dose (for example: combined hormone (contain estrogen and progesterone), combining inhibit ovulation, progestin contraception and inhibit ovulation, intrauterine device, intrauterine hormone release system, bilateral vasectomy, bilateral tubal ligation, avoiding sexual behavior, etc.); female subjects must have negative blood HCG (except menopause, hysterectomy or bilateral oophorectomy).
排除标准
- •AML occurs in any of the following situations:
- •Acute promyelocytic leukemia;
- •Chronic myeloid leukaemia in blast crisis;
- •Central nervous system (CNS) involvement with AML;
- •Subjects has been previously diagnosed with other malignant tumors in the past 5 years (except curable tumors such as basal cell carcinoma of the skin and carcinoma in situ of the cervix);
- •Graft-versus-host disease requiring ongoing treatment and having received more than one allogeneic stem cell transplant.
- •History of allergy to mitoxantrone hydrochloride injection or liposomal drugs;
- •Previous treatment with doxorubicin or other anthracycline and a cumulative dose of doxorubicin in excess of 400mg/m^2 (anthracycline equivalent dose calculation: 1 mg doxorubicin =2 mg epirubicin = 2 mg daunorubicin = 0.5 mg idarubicin = 0.45 mg mitoxantrone; Adriamycin liposomes excepted);
- •Received any antineoplastic therapy within 2 weeks prior to initial administration (or within 5 half-lives of the drug). Except for leukocyte lowering therapy (hydroxyurea, leukocyte separation, etc.) and prophylactic intrathecal injection which are over 24 hours prior to administration; 7.The non-hematologic toxicity of previous anti-tumor treatment > Grade 1 based on CTCAE (except for alopecia, skin pigmentation or tolerable events judged by the investigator);
- •Those on systemic anti-infective therapy with poorly controlled infection (signs of infection progression within 1 week prior to the first dose, or as determined by the investigator);
- •Life expectancy < 3 months;
- •Cardiovascular diseases, including but not limited to:
- •QTc interval >480 ms or long QTc syndrome in screening;
- •Complete left bundle branch block, severe atrioventricular block (without pacemaker);
- •Requiring treatment of serious and uncontrolled arrhythmias, unstable angina pectoris, valvular disease, etc;
- •Have a history of chronic congestive heart failure, New York Heart Association（NYHA）≥3; or persistent cardiomyopathy;
- •Uncontrolled hypertension (defined as multiple measurements of systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg under medication control);
- •ECG evidence of myocardial infarction, viral myocarditis, history of severe pericardial disease, acute ischemic or active conduction system abnormalities within 6 months prior to screening;
- •Severe thrombosis or thromboembolism in the past 6 months, including but not limited to cerebrovascular accident (including transient ischemic attack, etc.), upper/lower vena cava thrombosis, lower extremity deep vein thrombosis, pulmonary embolism, etc;
- •HBsAg or HBcAb positive, with HBV DNA≥2000 IU/mL, or HCV antibody positive with HCV RNA higher than the lower limit of the detection value of the research center, or HIV antibody positive in the preliminary screening;
- •Subjects are suffering from any other serious and/or uncontrollable disease that, in the judgment of the investigator, may affect the patient's participation in this study (including but not limited to: uncontrolled diabetes, kidney disease requiring dialysis treatment, severe liver diseases, life-threatening autoimmune disease and hemorrhagic disease, drug abuse, nervous system diseases, etc.);
- •Pregnant or lactating female;
- •Not suitable for this study as decided by the investigator due to other reasons
研究组 & 干预措施
Mitoxantrone Hydrochloride Liposome Injection
Stage 1: Subjects with R/R AML will receive one of three dose-escalation (30 mg/m^2, 36 mg/m^2, 40 mg/m^2) Mitoxantrone Hydrochloride Liposome, IV, on day 1 of each 28-day cycle (q4w).
Stage 2: Subjects with R/R AML or unfit AML will receive one dose Mitoxantrone Hydrochloride Liposome every 28 days (a cycle) for a maximum of 6 cycles.
干预措施: Mitoxantrone Hydrochloride Liposome (Drug)
结局指标
主要结局
DLT
时间窗: At the end of Cycle 1 (each cycle is 28 days)
Number of Participants with Dose Limiting Toxicities (DLTs, Stage 1)
CR
时间窗: From the initiation of the first dose to 28 days after the last dose
Complete remission (CR) rate (Stage 2)
次要结局
- TEAEs(From the initiation of the first dose to 28 days after the last dose)
- EFS(up to 36 months)
- ORR(At the end of Cycle 2 (each cycle is 28 days))
- Tmax(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)
- OS(From the enrollment to the death of last subject or the end of the clinical trial (up to 36 months))
- CL(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)
- Cmax(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)
- CR rate(From the initiation of the first dose to 28 days after the last dose)
- CRc(At the end of Cycle 2 (each cycle is 28 days))
- AUC0-t(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)
- AUC0-∞(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)
- t1/2(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)
- Vz(Within 1hour before IV administration of the first cycle to 1hour before the second cycle)