An Open-label Two Strata Study of Bisantrene in Combination With Cytarabine Arabinoside or Bisantrene in Combination With Oral Decitabine/Cedazuridine for the Treatment of Acute Myeloid Leukemia Patients With Extramedullary Disease
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Stratum 2: Safety and tolerabillity
研究概览
简要总结
This is a two strata Phase 1b study to assess the safety and efficacy of bisantrene (RC110) in combination with a) cytarabine arabinoside (Ara-C) treatment for patients with relapsed or refractory (R/R) Acute Myeloid Leukemia (AML) with extramedullary disease and able to tolerate intensive chemotherapy; b) in combination with decitabine/cedazuridune (ASTX727) new or relapsed or refractory AML or high risk MDS or CMML with extramedullary disease and unable or not willing to have intensive chemotherapy.
详细描述
The study is a multicenter, open label in patients with haematological malignancy / myeloproliferative disease (AML, MDS and CMML) and extramedullary disease (EMD) investigating 2 treatment regimens:
- Stratum 1 will investigate use of high dose intravenous (IV) bisantrene (RC110) in combination with IV Ara-C for R/R AML with EMD able to tolerate intensive chemotherapy. This includes a run-in stage to confirm the dose of bisantrene (RC110) for induction and in combination with Ara-C for consolidation cycles and an expansion and an expansion stage that will treat additional patients at the confirmed bisantrene dose for induction and in combination with Ara-C consolidation cycles;
- Stratum 2 will investigate use lower doses intravenous (IV) bisantrene (RC-110) in combination with fixed-dose oral decitabine/cedazuridine (ASTX727) to determine the maximum tolerated dose (MTD) for new or R/R AML and HR-MDS/CMML unable to tolerate intensive chemotherapy.
Pre-screening will be conducted to identify patients with EMD diagnosed by standard clinical practice including histology and by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F FDG-PET/CT) imaging.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •[Both Stratums]
- •Patients must be able to understand and provide informed written consent.
- •Patients must be of age ≥ 18 years at the time of signing the informed consent.
- •Extramedullary disease (i.e., AML) by 18F-FDG PET/CT and/or clinical morphology (histopathology of chloroma, leukemia cutis or AML) at pre-screening
- •Patients who have undergone stem cell transplantation (SCT), maybe included if they are ≥ 8 weeks from stem cell infusion (autologous or allogeneic), have no active graft versus host disease (GVHD), are off immune suppression for at least 2 weeks, and do not have a history of veno occlusive disease (VOD).
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.0 for intensive Stratum 1 patients and ≤ 3.0 for low intensity treatment Stratum 2 patients.
- •Life expectancy estimated to be > 3 months.
- •Adequate organ function as evidenced by serum total bilirubin ≤ 2.0 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 × the upper limit of normal (ULN), serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance of ≥ 60 mL/min.
- •Cardiac ejection fraction ≥ 50%, assessed by 2-Dimensional (2D) echocardiogram.
- •Females of childbearing potential must have a negative serum pregnancy test at enrolment or within 14 days before study entry and must agree to use an adequate method of contraception, i.e., barrier method, during the study until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception, i.e., barrier method, during the study until 30 days after the last treatment.
- •[Stratum 1 only]
- •Diagnosis of R/R AML, defined as ≥ 5% blasts in a patient with known prior history of AML according to World Health Organization (WHO) criteria. Patients with AML that have relapsed at least once or are primary induction failure will be eligible.
- •[Stratum 2 only]
- •Patients with diagnosis of de novo AML with EMD, or R/R AML with EMD.
- •Patients with MDS or CMML, diagnosed according to the 2016 WHO classification with high-risk disease per the International Prognostic Scoring System (IPSS) of intermediate 2 or higher for both MDS and CMML. Revised IPSS intermediate risk patients can be considered after discussion with the Investigator.
排除标准
- •[Both Stratums]
- •Acute promyelocytic leukemia (APML) M3 subtype of AML.
- •Central nervous system manifestations of AML, unless treated and with no residual manifestations (either by cerebrospinal fluid (CSF) cytology, radiologically or by other clinical assessments) in the last 2 weeks.
- •Evidence or recent history of CNS disease, including primary or metastatic brain tumors, seizure disorders unless there is evidence for clearance of CNS leukemia (2 leukemia free CSFs by morphology and /or flow cytometry 1 week apart).
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cirrhosis, chronic obstructive or restrictive pulmonary disease, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
- •Other active malignancy (including other hematologic malignancies) or other malignancy within the last 12 months except non-melanoma skin cancer or cervical intraepithelial neoplasia.
- •Major surgery within 4 weeks of treatment.
- •Any medical, psychological, or social condition that may interfere with study patient or compliance or may compromise the patient's safety in the opinion of the Investigator.
研究组 & 干预措施
Stratum 1
Bisantrene infused daily for 7 days of induction cycle 1; followed by bisantrene infusion on Days 1 and 2 and cytarabine arabinoside continuous infusion on Days 1 to 5 of each consolidation cycle for up to 3 cycles.
Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery.
干预措施: Bisantrene Dihydrochloride (high dose) (Drug)
Stratum 1
Bisantrene infused daily for 7 days of induction cycle 1; followed by bisantrene infusion on Days 1 and 2 and cytarabine arabinoside continuous infusion on Days 1 to 5 of each consolidation cycle for up to 3 cycles.
Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery.
干预措施: Cytarabine Hydrochloride (Drug)
Stratum 2
Decitabine/cedazuridine daily on Days 1-5, Bisantrene infusion on Days 3 and 5 in 28 day cycle. Treatment repeats every 28 days up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Each has potential to expand to 42 days to allow for full hematologic recovery.
干预措施: Bisantrene Dihydrochloride (low dose) (Drug)
Stratum 2
Decitabine/cedazuridine daily on Days 1-5, Bisantrene infusion on Days 3 and 5 in 28 day cycle. Treatment repeats every 28 days up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Each has potential to expand to 42 days to allow for full hematologic recovery.
干预措施: Decitabine and cedazuridine (Drug)
结局指标
主要结局
Stratum 2: Safety and tolerabillity
时间窗: 4 weeks
Assessed based on the occurence of non-hematological Dose limiting toxicity (DLT) as graded according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE) for Adverse Events v5.0 at the completion of cycle 1.
Stratum 1, Stage 1: Dose confirmation
时间窗: 8 weeks
Maximum tolerated dose (MTD) based on occurence dose limiting toxicity (DLT) graded according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE) for Adverse Events v5.0 after completion of 2 cycles of treatment
Stratum 1 Stage 2: Overall response
时间窗: 4 weeks
Morphological overall response, defined as complete remission (CR), CR with incomplete hematologic recovery or morphologic leukemia free state (MLFS), after completion of first treatment cycle 1
次要结局
- Stratum 1:Event free survival (EFS)(Day 1 (treatment start) to 5 years)
- Stratum 1: Dermal clinical response(4, 8, 12, and 16 weeks)
- Stratum 1: Dermal therapeutic response(4, 8, 12, and 16 weeks)
- Stratum 1: Safety and tolerability(4, 8, 12 and 16 weeks)
- Stratum 1: Number of participants that recieve subsequent allogeneic hematopoietic stem cell transplant(5 years)
- Stratum 2: Overall response(4 weeks)
- Stratum 2: Minimal Residual Disease (MRD) response(16 weeks)
- Stratum 2: Radiologic response(16, 36 and 48 weeks)
- Stratum 2: Dermal clinical response(4, 24, 36 and 48 weeks)
- Stratum 2: Dermal therapeutic response(4, 24, 36 and 48 weeks)
- Stratum 1: Minimal Residual Disease (MRD) response(4 weeks)
- Stratum 1: Radiologic response(4, 8 and 16 weeks)
- Stratum 1: Overall Survival (OS)(Day 1 (treatment start) to 5 years)
- Stratum 2: Event free survival (EFS)(Day 1 (treatment start) up to 5 years)
- Stratum 2: Overall survival (OS)(Day 1 (treatment start) to 5 years)