Clinical trial NCT05658640: HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Lymphoblastic Leukemia, in Relapse
Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent
Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent
Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Refractory
Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Refractory
Keywords: Acute lymphoblastic leukemia
Lymphoblastic lymphoma
Biomarker driven clinical trial
Trametinib
Chemotherapy
Relapse
Refractory
Children
Adolescents
Young adults
Lead sponsor: Princess Maxima Center for Pediatric Oncology
Sponsor class: OTHER
Collaborators: name: Innovative Therapies For Children with Cancer Consortium
name: IBFM
name: Fight Kids Cancer
First posted: 2022-12-21
Enrollment: 26
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion criteria

1. Children between 1 year (≥ 12 months) and 18 years of age at the time of first diagnosis and less than 21 years at the time of inclusion. Patients under 6 years old must weigh at least 7 kg at the time of enrollment. Patients over 6 years old must weigh at least 10 kg at the time of enrollment.
2. Performance status: Karnofsky performance status (for patients \>12 years of age) or Lansky Play score (for patients

   * 12 years of age) ≥ 50% (Appendix I).
3. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study specific screening procedures are conducted, according to local, regional or national guidelines.
4. Patients must have had molecular profiling and flow-cytometric analysis of their recurrent or refractory disease at a time-point before the first inclusion into this trial (see section 9.1 of this protocol for detailed description of the molecular diagnostics required). Drug response profiling and methylation is highly recommended but not mandatory.

   Patients with molecular profiling at first diagnosis lacking molecular diagnostics at relapse or refractory disease may be allowed to be included after discussion with the sponsor.
5. Patients whose tumor present RAS pathway activating mutations including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del, as detected by molecular profiling.
6. Adequate organ function:

   * RENAL AND HEPATIC FUNCTION (Assessed within 48 hours prior to C1D1) :

     * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age or calculated creatinine clearance as per the Schwartz formula or radioisotope glomerular filtration rate ≥ 60 mL/min/1.73 m2.
     * Direct bilirubin ≤ 2 x ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome).
     * Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 5 x ULN. Note: Patients with hepatic disfunction related to the underling disease can be eligible even if they do not fulfill the aforementioned values for hepatic transaminases. In these cases, patients need to be discussed with the sponsor to confirm the eligibility.
   * CARDIAC FUNCTION:

     * Shortening fraction (SF) \>29% (\>35% for children \< 3 years) and/or left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography or MUGA.
     * Absence of QTcF prolongation (QTc prolongation is defined as \>450 msec on baseline ECG, using the Fridericia correction), or other clinically significant ventricular or atrial arrhythmia.

   Exclusion Criteria
7. Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1.
8. Sexually active participants not willing to use highly effective contraceptive method (pearl index \<1) as defined in CTFG HMA 2020 (Appendix II) during trial participation and until 6 months after end of antileukemic therapy.
9. Breast feeding.
10. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome) in case of oral IMPs.
11. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drugs, or drugs chemically related to study treatment or excipients that contraindicate their participation, including conventional chemotherapeutics (i.e. cytarabine and cyclophosphamide, intrathecal agents) and corticoids.
12. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
13. Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion.
14. Subjects unwilling or unable to comply with the study procedures.
15. Previous treatment with trametinib.
16. Current use of a prohibited medication or herbal preparation or requires any of these medications during the study.

    See Section 7 and Appendix III for details. Drugs inducing QTc changes (prolongation of the QT interval or inducing Torsade de Points) are not permitted.
17. Unresolved toxicity greater than NCI CTCAE v 5.0 ≥ grade 2 from previous anti-cancer therapy, including major surgery, except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of the study treatment (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy) (Common Terminology Criteria for Adverse Events (CTCAE) (cancer.gov).
18. Active acute graft versus host disease (GvHD) of any grade or chronic GvHD of grade 2 or higher. Patients receiving any agent to treat or prevent GvHD post bone marrow transplant are not eligible for this trial.
19. Received immunosuppression post allogenic HSCT within one moth of study entry.
20. History or current evidence of retina vein occlusion (RVO) or central serous retinopathy are excluded.
21. Wash-out periods of prior medication:

    1. CHEMOTHERAPY: At least 7 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine, oral methotrexate and steroids which are permitted up until 48 hours prior to initiating protocol therapy. Patients may have received intrathecal therapy (IT) at any time prior to study entry.
    2. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed.
    3. HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): Autologous HSCT within 2 months prior to the first study drug dose; Allogeneic HSCT within 3 months prior to the first study drug dose.
    4. IMMUNOTHERAPY: At least 42 days must have elapsed after the completion of any type of immunotherapy other than monoclonal antibodies (e.g. CAR-T therapy)
    5. MONOCLONAL ANTIBODIES AND INVESTIGATIONAL DRUGS: At least 21 days or 5 times the half-life (whichever is shorter) from prior treatment with monoclonal antibodies or any investigational drug under investigation must have elapsed before the first study drug.
    6. SURGERY: Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery.

Primary outcomes:
measure: Phase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D)
timeFrame: 3 years
measure: Phase II: Best Overall Response Rate (ORR)
timeFrame: 6 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 7 years
measure: Event-free survival (EFS)
timeFrame: 7 years
measure: Cumulative incidence of relapse (CIR)
timeFrame: 7 years
measure: Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy
timeFrame: 7 years
measure: Cumulative overall response rate (ORR)
timeFrame: 7 years
measure: Rate of dose limiting toxicities (DLTs)
timeFrame: 7 years
measure: Peak Plasma Concentration (Cmax)
timeFrame: 6 years
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: St. Anna Kinderspital
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Copenhagen
country: Denmark
facility: Rigshospitalet Copenhagen
city: Helsinki
country: Finland
facility: Helsinki University Hospital, New Children's Hospital
city: Bordeaux
country: France
facility: Hôpital des Enfants GH Pellegrin - CHU de Bordeaux
city: Lille
country: France
facility: CHRU Lille - Hôpital Jeanne de Flandre
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hopital La Timone - Enfants
city: Nantes
country: France
facility: CHU Nantes Hôpital Mère-Enfant
city: Paris
country: France
facility: Hôpital Robert Debré
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children
city: Petach Tikva
country: Israel
facility: Schneider's Children's Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center Hospital
city: Genova
country: Italy
facility: IRCCS Istituto Giannina Gaslini
city: Monza
country: Italy
facility: Fondazione MBBM c/o Centro ML Verga
city: Padova
country: Italy
facility: Padova Azienda Ospedaliera
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù, IRCCS
city: Turin
country: Italy
facility: Ospedale Infantile Regina Margherita
city: Utrecht
country: Netherlands
facility: Princess Máxima Center for Pediatric Oncology
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu de Barcelona
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesús
city: Valencia
country: Spain
facility: La Fe
city: Stockholm
country: Sweden
facility: Karolinska university hospital
city: Zürich
country: Switzerland
facility: University Children's Hospital Zürich
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Newcastle
country: United Kingdom
facility: Great North Children's Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Trust
Study officials:
affiliation: Princess Máxima Center
name: Paco Bautista, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Princess Máxima Center
name: Michel Zwaan, Prof. dr.
role: STUDY_CHAIR
References: