A Phase 3, Open-Label, Multicenter, Randomized Study of SKLB1028 Versus Salvage Chemotherapy in Patients With FLT3-mutated Acute Myeloid Leukemia Refractory to or Relapsed After First-line Treatment（ALIVE）
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 315
- 试验地点
- 1
- 主要终点
- Interim analysis: CR/CRh rate in the experimental group.
研究概览
简要总结
This is a randomized，multicenter, open-label Phase III, clinical study to confirm the efficacy and safety of SKLB1028 in patients with relapsed or refractory(R/R) FLT3-Mutated Acute Myeloid Leukemia（AML）compared to salvage chemotherapy.
详细描述
Eligible subjects will be randomized in a 2:1 ratio to receive SKLB1028 or salvage chemotherapy. Subjects will enter the screening period up to 14 days before the start of treatment. Prior to randomization, a salvage chemotherapy regimen will be pre-selected for each subject. Options will include low-dose cytarabine (LoDAC), azacitidine, homoharringtonine (HHT), cytarabine and aclarubicin (HAA) or fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG). The randomization will be stratified by indications and intensity of pre-selected salvage chemotherapy.
Subjects will be orally administrated SKLB1028 twice daily over continuous 28-day cycles . Subjects in the salvage chemotherapy group will receive chemotherapy as required by the guidelines. Subjects receiving SKLB1028, LoDAC, or azacytidine will continue to receive the treatment until a treatment discontinuation criterion is met. Subjects receiving HAA or FLAG will take 1 cycle of therapy and will be assessed for response after the 1st cycle. After the efficacy evaluation, the subject may receive a second cycle of chemotherapy at the investigator's discretion. will receive the second cycle of chemotherapy.
Subjects who have a donor identified and with complete remission after treatment may undergo hematopoietic stem cell transplant (HSCT) without leaving the study. Subjects in the salvage chemotherapy group who withdrew due to non-response to treatment or disease progression, could switch to SKLB1028 if SKLB1028 will likely benefit the patient at the investigator's discretion.
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
- 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
- •Patients volunteered to participate in this study and signed the informed consent form.
- •Age≥18 years old, no gender limitation.
- •Patient has a diagnosis of primary AML or AML secondary to myelodysplastic syndrome (MDS) as determined by pathological and morphological results, according to World Health Organization (WHO) 2016 classification.
- •Patient is refractory to or relapsed after first-line AML therapy (with or without HSCT).
- •Refractory to first-line AML treatment is defined as: the patient did not achieve complete remission/complete remission with incomplete hematologic recovery/complete remission with incomplete platelet recovery (CR/CRi/CRp) under initial therapy. A patient eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction therapy in the standard dose for the selected induction regimen. A patient not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this patient as per investigator's assessment.
- •Early relapse after first-line AML therapy is defined as: the patients achieved CR/CRi/CRp after first-line treatment, and relapsed within 6 months with hematological relapse.
- •Advanced relapse after first-line AML therapy is defined as: the patients achieved CR/CRi/CRp after first-line treatment and relapsed after 6 months with hematological relapse;
- •Patient is positive for FLT3 mutation in bone marrow or whole blood.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Patient is eligible for pre-selected salvage chemotherapy according to investigator assessment.
- •Patient must meet the following criteria as indicated on the clinical laboratory tests:
- •Serum aspartate aminotransferase and alanine aminotransferase ≤ 3.0 x upper limit of normal (ULN);
- •Serum total bilirubin ≤ 1.5 x ULN;
- •Serum creatinine ≤ 3.0 x ULN or an estimated glomerular filtration rate of > 30 mL/min.
- •Patient is suitable for oral administration of the study drug.
- •Female or male patient of childbearing age agree to take effective non-drug contraception from the date of signing an informed consent to 180 days after the last dose and will not donate sperm or eggs.
排除标准
- •Patient was diagnosed as acute promyelocytic leukemia (APL), or BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
- •Patient has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
- •AML with central nervous system (CNS) involvement (defined as highly suspected CNS involvement with clinical symptoms supported by imaging evidence).
- •Refractory hypokalemia or hypomagnesemia that is difficult to be corrected by symptomatic treatment and has recurred in the past.
- •Patient is currently suffering from clinically significant graft-versus-host disease (GVHD) or receiving systemic cortisol hormone therapy for GVHD.
- •Patient has been previously diagnosed with another malignancy (except in the following cases: disease-free for at least 5 years; Patients with treated nonmelanoma skin cancer, breast in situ carcinoma or cervical intraepithelial neoplasia [regardless of disease status]; Localized prostate cancer with no recurrence or progression that is expected to be cured after treatment, such as radiotherapy or surgery)
- •Patient has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation (DIC), hemophilia A, hemophilia B, and von Willebrand disease.
- •Patient has had major surgery within 4 weeks prior to the study (the definition of major surgery was based on the level 3 and level 4 surgeries stipulated in the Management Measures for Clinical Application of Medical Technology), or has not fully recovered from any previous invasive operation.
- •Patient has radiation therapy within 4 weeks before the first study dose.
- •Patient has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or patient with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 1 month before study entry results in a left ventricular ejection fraction that is ≥ 45%.
- •Patient has bradycardia and heart rate is less than 50 beats/min, except for pacemaker user.
- •Patients with mean value of triplicate Fridericia-corrected QT interval (QTcF) in the screening period, male > 450 ms, female > 470 ms.
- •Patients with diagnosed or suspected long QT syndrome at screening (including a family history of long QT syndrome).
- •Patients with second degree (Mobitz II) or third degree atrioventricular block disease (except for patients who use the pacemaker).
- •Patients with uncontrolled angina or myocardial infarction in 6 months before screening.
- •Patient has a complete left bundle branch block during screening.
- •Patients with new clinically significant arrhythmias (except for sinus tachycardia caused by anemia, infection and AML) or patients with previous arrhythmias that require long-term use of drugs with QT-prolonging effects.
- •Patient has an active uncontrolled infection.
- •Patients are hepatitis B surface antigen-positive or have a history of hepatitis B, with HBV-DNA ≥2000 IU/mL in the past 3 months; Patients are hep
- •Patients with positive anti-human immunodeficiency virus antibodies or anti-Treponema pallidum specific antibodies.
- •Patient has cytotoxic chemotherapy drugs <2 weeks, or non-cytotoxic drugs <5 half-lives prior to the first study dose (except hydroxyurea and other treatments used to control hyperleucocytosis).
- •Patients have taken CYP 2C8 and CYP 3A4 strong inducers or inhibitors within 2 weeks prior to the first study dose.
- •Patients have previously received other FLT3 inhibitors (Gilteritinib, Quizatinib, Crenolanib, etc.), except for sorafenib.
- •Pregnant (blood pregnancy test positive in screening period) and lactating Female.
- •Patients are not suitable for the study in the investigator's opinion.
研究组 & 干预措施
SKLB1028
Subjects will receive 150 mg orally twice daily (BID) in continuous 28-day cycles
干预措施: SKLB1028 (Drug)
Salvage Chemotherapy
Chemotherapy will be given in 28-day cycles. Subjects on low-dose cytarabine (LoDAC) will receive 10 to 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injections for 7 to 14 days.
Subjects on azacitidine will receive 75 mg/m^2 daily by SC or IV, for 5 to 7 days.
Subjects on homoharringtonine (HHT), cytarabine and aclarubicin (HAA) will receive 2 mg/m^2 of HHT by IV, for 7 days (day 1 to 7) (or HHT 2 mg/m^2, twice daily, day 1 to 3); 100~200 mg/m^2 of cytarabine by IV for 7 days (day 1~7) and 20 mg/d of aclarubicin by IV for 7 days (day 1 to 7).
Subjects on fludarabine, cytarabine and granulocyte colony-stimulating factor (G-CSF) (FLAG) will receive 30 mg/m^2 of fludarabine daily by IV for 5 days (day 2 to 6), 1000~2000 mg/m2 of cytarabine daily by IV for 5 days (day 2 to 6), and 300 g/m^2 of G-CSF daily by SC or IV for 5 days (days 1 to 5). After completion of chemotherapy, G-CSF will be administered continually until ANC>0.5 x 10^9 / L.
干预措施: Salvage Chemotherapy (Drug)
结局指标
主要结局
Interim analysis: CR/CRh rate in the experimental group.
时间窗: up to 4 years.
The complete remission and complete remission with partial hematological recovery (CR/CRh) rate was defined as the number of subjects who achieved either CR or CRh divided by the number of subjects in the response analysis set (RAS).
The final analysis: Overall Survival(OS)
时间窗: up to 4 years.
Overall survival was defined as the time from the date of randomization until the date of death from any cause.
次要结局
- Key secondary end point: Event-Free Survival (EFS).(up to 4 years.)
- Duration of remission (DOR).(up to 4 years.)
- Duration of Leukemia-Free Survival (LFS)(up to 4 years.)
- Composite complete remission rate(up to 4 years.)
- Time to CR(TTR)(up to 4 years.)
- Transplantation rate(up to 4 years.)
- Transfusion conversion rate and transfusion-Independence rate.(up to 4 years.)
- Safety assessed by adverse events.(up to 4 years.)
- Population pharmacokinetic of SKLB1028(Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1: predose. A cycle is 28 days.)