HEM-iSMART: International clinical study for children and adolescents with relapsed or refractory leukemia or lymphoma with specific mutations. HEM-iSMART Subprotocol B (NCT05751044): Dasatinib and Venetoclax for children with relapsed or refractory leukemia or lymphoma with a MAPK/SRC signaling pathway mutation HEM-iSMART Subprotocol C (NCT05745714): Ruxolitinib and Venetoclax for children with relapsed or refractory leukemia or lymphoma with an IL7R/JAK-STAT mutation HEM-iSMART Subprotocol D (NCT05658640): Trametinib for children with relapsed or refractory leukemia or lymphoma with a RAS mutation

Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom (ICTRP)

Identifiant de l'essai ICTRP
NCT05658640 (ICTRP)

Titre officiel (approuvé par le comité d'éthique)
ITCC-104: HEM-iSMART International proof of concept therapeutic Stratification trial of Molecular Anomalies in Relapsed or Refractory HEMatological malignancies in children (BASEC)

Titre académique
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 (ICTRP)

Titre public
HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies (ICTRP)

Maladie en cours d'investigation
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 (ICTRP)

Intervention étudiée
Drug: Trametinib;Drug: Dexamethasone;Drug: Cyclophosphamide;Drug: Cytarabine;Drug: Intrathecal chemotherapy (ICTRP)

Type d'essai
Interventional (ICTRP)

Plan de l'étude
Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Critères d'inclusion/exclusion
Gender: All
Maximum age: 21 Years
Minimum age: 1 Year
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. (ICTRP)

non disponible

Critères d'évaluation principaux et secondaires
Phase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D);Phase II: Best Overall Response Rate (ORR) (ICTRP)

Overall survival (OS);Event-free survival (EFS);Cumulative incidence of relapse (CIR);Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy;Cumulative overall response rate (ORR);Rate of dose limiting toxicities (DLTs);Peak Plasma Concentration (Cmax) (ICTRP)

Date d'enregistrement
24.11.2022 (ICTRP)

Inclusion du premier participant
non disponible

Sponsors secondaires
Innovative Therapies For Children with Cancer Consortium;IBFM;Fight Kids Cancer (ICTRP)

Contacts supplémentaires
Paco Bautista, MD PhD;Michel Zwaan, Prof. dr.;Anne Elsinghorst, hem-ismart@prinsesmaximacentrum.nl, +316 5000 6270, Princess M?xima Center,Princess M?xima Center, (ICTRP)

ID secondaires
2021-003398-79 (ICTRP)

Résultats-Données individuelles des participants
non disponible

Informations complémentaires sur l'essai
https://clinicaltrials.gov/ct2/show/NCT05658640 (ICTRP)