International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol D: Trametinib + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 26
- 试验地点
- 36
- 主要终点
- Phase II: Best Overall Response Rate (ORR)
研究概览
简要总结
HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol D is a phase I/II trial evaluating the safety and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the RAS-RAF-MAPK pathway.
详细描述
HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia.
Sub-Protocol D within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the RAS-RAF-MAPK pathway will be eligible for sub-protocol D including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del.
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
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Sub-study D
Trametinib + dexamethasone + cyclophosphamide and cytarabine.
Each cycle lasts 28 days.
Cycle 1: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 3. Cytarabine is given IV in two blocks of 4 days each one week apart from day 5.
Cycle 2 and subsequent cycles: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 1. Cytarabine is given IV in two blocks of 4 days each one week apart from day 3.
Patients in dose level -1, receive only 1 block of cytarabine per cycle.
All patients receive age adapted intrathecal chemotherapy.
干预措施: Trametinib (Drug)
Sub-study D
Trametinib + dexamethasone + cyclophosphamide and cytarabine.
Each cycle lasts 28 days.
Cycle 1: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 3. Cytarabine is given IV in two blocks of 4 days each one week apart from day 5.
Cycle 2 and subsequent cycles: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 1. Cytarabine is given IV in two blocks of 4 days each one week apart from day 3.
Patients in dose level -1, receive only 1 block of cytarabine per cycle.
All patients receive age adapted intrathecal chemotherapy.
干预措施: Dexamethasone (Drug)
Sub-study D
Trametinib + dexamethasone + cyclophosphamide and cytarabine.
Each cycle lasts 28 days.
Cycle 1: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 3. Cytarabine is given IV in two blocks of 4 days each one week apart from day 5.
Cycle 2 and subsequent cycles: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 1. Cytarabine is given IV in two blocks of 4 days each one week apart from day 3.
Patients in dose level -1, receive only 1 block of cytarabine per cycle.
All patients receive age adapted intrathecal chemotherapy.
干预措施: Cyclophosphamide (Drug)
Sub-study D
Trametinib + dexamethasone + cyclophosphamide and cytarabine.
Each cycle lasts 28 days.
Cycle 1: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 3. Cytarabine is given IV in two blocks of 4 days each one week apart from day 5.
Cycle 2 and subsequent cycles: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 1. Cytarabine is given IV in two blocks of 4 days each one week apart from day 3.
Patients in dose level -1, receive only 1 block of cytarabine per cycle.
All patients receive age adapted intrathecal chemotherapy.
干预措施: Cytarabine (Drug)
Sub-study D
Trametinib + dexamethasone + cyclophosphamide and cytarabine.
Each cycle lasts 28 days.
Cycle 1: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 3. Cytarabine is given IV in two blocks of 4 days each one week apart from day 5.
Cycle 2 and subsequent cycles: Trametinib is given orally continuously once a day in tablets or oral formulation depending on the age and weight of the patient. Dexamethasone is given intravenously (IV)/orally on days 1 to 5. Cyclophosphamide is given IV on day 1. Cytarabine is given IV in two blocks of 4 days each one week apart from day 3.
Patients in dose level -1, receive only 1 block of cytarabine per cycle.
All patients receive age adapted intrathecal chemotherapy.
干预措施: Intrathecal chemotherapy (Drug)
结局指标
主要结局
Phase II: Best Overall Response Rate (ORR)
时间窗: 6 years
For patients with leukemia: CR and MRD response after 1 cycle of treatment. This includes determination of CR, CRp, CRi and minimal residual disease (MRD) negativity rate in patients suffering from overt morphological relapse of T-ALL at time of enrolment (morphological disease (M2/M3)), and the MRD negativity rate in those that entered with high-MRD levels but in morphological CR. These results will together be presented as a composite endpoint Overall Response rate (ORR). MRD negativity will be defined as ≤1x10-4 as generated by multi-parameter flow cytometry. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria. In case of bone-marrow involvement MRD will be taken into account. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria
Phase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D)
时间窗: 3 years
Defined as the highest dose level tested at which 0/6 or 1/6 patients experiences dose limiting toxicities (DLT) during course 1 with at least 2 patients experiencing DLT at the next higher dose
次要结局
- Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy(7 years)
- Overall survival (OS)(7 years)
- Event-free survival (EFS)(7 years)
- Cumulative incidence of relapse (CIR)(7 years)
- Cumulative overall response rate (ORR)(7 years)
- Peak Plasma Concentration (Cmax)(6 years)
- Rate of dose limiting toxicities (DLTs)(7 years)