HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies
- Conditions
- Acute Lymphoblastic Leukemia, in RelapseLymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) RecurrentLymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) RefractoryLymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) RefractoryLymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent
- Interventions
- Drug: Intrathecal chemotherapy
- Registration Number
- NCT05658640
- Lead Sponsor
- Princess Maxima Center for Pediatric Oncology
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 26
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Sub-study D Trametinib 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. Sub-study D Intrathecal chemotherapy 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. Sub-study D Dexamethasone 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. Sub-study D Cyclophosphamide 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. Sub-study D Cytarabine 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.
- Primary Outcome Measures
Name Time Method Phase II: Best Overall Response Rate (ORR) 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 criteriaPhase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D) 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
- Secondary Outcome Measures
Name Time Method Overall survival (OS) 7 years Defined as time from C1D1 until death of any cause.
Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy 7 years The rate of those proceeding to subsequent allogenic HSCT
Event-free survival (EFS) 7 years Defined as time from C1D1 to the first event (subsequent relapse after CR (including molecular reappearance), death of any cause, failure to achieve remission (CR, CRp or CRi), or secondary malignancy)
Cumulative incidence of relapse (CIR) 7 years Estimate of the risk, that a patient will develop a relapse over a specified period of time.
Cumulative overall response rate (ORR) 7 years Defined as the CR, CRp, CRi and MRD negativity rates after more than 1 cycle of treatment.
Peak Plasma Concentration (Cmax) 6 years Estimation of trametinib CMAX
Rate of dose limiting toxicities (DLTs) 7 years Number of participants with dose limiting toxicities (DLTs)
Trial Locations
- Locations (36)
St. Anna Kinderspital
🇦🇹Vienna, Austria
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Rigshospitalet Copenhagen
🇩🇰Copenhagen, Denmark
Helsinki University Hospital, New Children's Hospital
🇫🇮Helsinki, Finland
Hôpital des Enfants GH Pellegrin - CHU de Bordeaux
🇫🇷Bordeaux, France
CHRU Lille - Hôpital Jeanne de Flandre
🇫🇷Lille, France
Centre Léon Bérard
🇫🇷Lyon, France
Hopital La Timone - Enfants
🇫🇷Marseille, France
CHU Nantes Hôpital Mère-Enfant
🇫🇷Nantes, France
Hôpital Robert Debré
🇫🇷Paris, France
Universitätsklinikum Augsburg
🇩🇪Augsburg, Germany
Charité Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Universitätsklinikum Essen
🇩🇪Essen, Germany
Universitätsklinikum Frankfurt
🇩🇪Frankfurt, Germany
Universitätsklinikum Münster
🇩🇪Münster, Germany
Our Lady's Hospital for Sick Children
🇮🇪Dublin, Ireland
Sheba Medical Center Hospital
🇮🇱Ramat Gan, Israel
Schneider's Children's Medical Center
🇮🇱Petach Tikva, Israel
IRCCS Istituto Giannina Gaslini
🇮🇹Genova, Italy
Fondazione MBBM c/o Centro ML Verga
🇮🇹Monza, Italy
Padova Azienda Ospedaliera
🇮🇹Padova, Italy
Ospedale Pediatrico Bambino Gesù, IRCCS
🇮🇹Roma, Italy
Ospedale Infantile Regina Margherita
🇮🇹Turin, Italy
Princess Máxima Center for Pediatric Oncology
🇳🇱Utrecht, Netherlands
Oslo University Hospital
🇳🇴Oslo, Norway
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Sant Joan de Déu de Barcelona
🇪🇸Barcelona, Spain
Hospital Infantil Universitario Niño Jesús
🇪🇸Madrid, Spain
La Fe
🇪🇸Valencia, Spain
Karolinska university hospital
🇸🇪Stockholm, Sweden
University Children's Hospital Zürich
🇨🇭Zürich, Switzerland
Bristol Royal Hospital for Children
🇬🇧Bristol, United Kingdom
Great Ormond Street Hospital for Children NHS Trust
🇬🇧London, United Kingdom
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Great North Children's Hospital
🇬🇧Newcastle, United Kingdom
Royal Marsden NHS Trust
🇬🇧Sutton, United Kingdom