Phase I/II Study of Sensitization of Non-M3 Acute Myeloid Leukemia (AML) Blasts to All-trans Retinoic Acid (ATRA) by Epigenetic Treatment With Tranylcypromine (TCP), an Inhibitor of the Histone Lysine Demethylase 1 (LSD1)
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 60
- 试验地点
- 6
- 主要终点
- MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;
研究概览
简要总结
The objective of the phase I part of the trial is the determination of the maximum tolerated dose (MTD) of TCP (Tranylcypromine) in combination with fixed-dose ATRA (all-trans-retinoic acid) and with fixed-dose AraC (Cytarabine) and to derive the recommended phase II dose (RP2D) in patients with non-APL AML or MDS for whom no standard treatment is available or who failed azanucleoside treatment.
The objective of the phase II part of the trial is a first evaluation of the efficacy of TCP at the RP2D in combination with fixed-dose ATRA and with fixed-dose AraC as basis for further investigations of TCP
详细描述
Study treatment: TCP + ATRA + AraC Four dose levels of TCP (20 mg, 40 mg, 60 mg, 80 mg on days 1-28) will be examined in combination with fixed dose ATRA (45 mg/m2 on days 10-28) and fixed-dose AraC (40 mg on days 1-10) in the first cycle.
In further cycles patients will be treated in the same manner, except for ATRA which will be administered continuously with a nine-day interruption at the beginning of every fourth cycle.
Follow-up per patient: Until twelve months after registration of the last patient.
Duration of intervention per patient: Until relapse/progression, unacceptable toxicity or until twelve months after registration of the last patient, whatever occurs first
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
- •Patients eligible for inclusion in this trial must meet all of the following criteria:
- •Patients >18 years (no upper age limit);
- •AML (WHO) or intermediate or higher risk MDS/ Chronic Myelomonocytic Leukemia (CMML) (IPSS-R >3.0);
- •No standard treatment available (comorbidities, higher age, refractoriness to standard or salvage chemotherapy and allografting, azanucleosides failure*);
- •Patients with < 30.000 leukocytes/µl;
- •Eastern Cooperative Oncology Group (ECOG) 0,1,2;
- •Written informed consent obtained according to international guidelines and local laws;
- •Ability to understand the nature of the trial and the trial related procedures and to comply with them.
- •Azanucleosides failure is defined as 1) no response after at least three (AML) or six (MDS) cycles of azacitidine or decitabine, 2) disease progression under treatment or 3) grade 3-4 non-hematologic toxicity.
排除标准
- •Patients eligible for this trial must not meet any of the following criteria:
- •Acute promyelocytic leukemia (APL, French-American-British classification system (FAB) M3);
- •Eligibility for standard induction or consolidation chemotherapy, immediate allografting, or a hypomethylating agent;
- •AML with central nervous system (CNS) involvement;
- •AraC treatment within one month prior to registration;
- •Prior exposure to histone deacetylase inhibitors, including sodium valproate within one month prior to registration;
- •Stem cell transplant patient with graft-versus-host disease (GvHD) or under systemic immunosuppression;
- •Previous gastrointestinal surgery that might interfere with drug absorption;
- •Pheochromocytoma;
- •Carcinoid tumor;
- •Confirmed or suspected cerebrovascular disease;
- •Vascular malformations including aneurysm;
- •Severe renal insufficiency;
- •Severe or poorly controlled hypertension;
- •Severe cardiovascular disease;
- •Hepatic insufficiency/liver disease;
- •Diabetes insipidus;
- •History or presence of malignant hyperthermia;
- •Known psychiatric disorders;
- •Known allergy against soy beans or peanuts;
- •Known hypersensitivity to or intolerance of one of the trial drugs or its constituents (e.g. lactose, corn starch, indigocarmine (TCP), corn starch (AraC), other retinoids (ATRA));
- •Simultaneous intake of the prohibited medication, incl. linezolid, that is likely to cause interactions (see detailed list study protocol);
- •Patients who refuse to follow study-specific dietary guidelines;
- •Known or persistent abuse of medication, drugs or alcohol;
- •Current or planned pregnancy, nursing period;
- •Failure to use safe methods of contraception;
- •Simultaneous participation in other interventional trials which could interfere with this trial and/or participation before the end of a required restriction period;
- •Participation in a clinical trial within the last 30 days before the start of this trial
- •Persons who are in a relationship of dependence/employment with the sponsor or the investigator;
研究组 & 干预措施
TCP, ATRA, Cytarabine
Phase I part:
The rolling-six phase I design will be used to determine the MTD of TCP in combination with fixed-dose of ATRA and with fixed-dose AraC in patients with AML/MDS.
Intervention: Four dose levels of TCP (20 mg, 40 mg**, 60 mg**, 80 mg** on days 1-28) will be examined in combination with ATRA (45 mg/m2 on days 10-28) and with fixed-dose AraC (40 mg on days 1-10) in the first cycle. In case of dose-limiting toxicity (DLT) on the starting level 1 of 20 mg a de-escalation to dose level of 10 mg (level -1) will be investigated.
**TCP dose will be slowly increased to achieve the necessary dose level and slowly tapered off at the end of treatment
干预措施: tranylcypromine (Drug)
TCP, ATRA, Cytarabine
Phase I part:
The rolling-six phase I design will be used to determine the MTD of TCP in combination with fixed-dose of ATRA and with fixed-dose AraC in patients with AML/MDS.
Intervention: Four dose levels of TCP (20 mg, 40 mg**, 60 mg**, 80 mg** on days 1-28) will be examined in combination with ATRA (45 mg/m2 on days 10-28) and with fixed-dose AraC (40 mg on days 1-10) in the first cycle. In case of dose-limiting toxicity (DLT) on the starting level 1 of 20 mg a de-escalation to dose level of 10 mg (level -1) will be investigated.
**TCP dose will be slowly increased to achieve the necessary dose level and slowly tapered off at the end of treatment
干预措施: all-trans retinoic acid (Drug)
TCP, ATRA, Cytarabine
Phase I part:
The rolling-six phase I design will be used to determine the MTD of TCP in combination with fixed-dose of ATRA and with fixed-dose AraC in patients with AML/MDS.
Intervention: Four dose levels of TCP (20 mg, 40 mg**, 60 mg**, 80 mg** on days 1-28) will be examined in combination with ATRA (45 mg/m2 on days 10-28) and with fixed-dose AraC (40 mg on days 1-10) in the first cycle. In case of dose-limiting toxicity (DLT) on the starting level 1 of 20 mg a de-escalation to dose level of 10 mg (level -1) will be investigated.
**TCP dose will be slowly increased to achieve the necessary dose level and slowly tapered off at the end of treatment
干预措施: cytarabine (Drug)
结局指标
主要结局
MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;
时间窗: first 28 days of treatment
MTD determination of TCP in combination with fixed-dose of ATRA and with fixed-dose Cytarabine;
次要结局
- Objective best response(through study completion, an average of one year)
- Overall survival (OS)(12 months)
研究者
Michael Luebbert
Prof. Dr. med.
University Hospital Freiburg