Home › Trials › NCT05658640

Combination treatment for children with relapsed or refractory blood cancers

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

Phase1; Phase2 Interventional Princess Maxima Center for Pediatric Oncology · NCT05658640

This study is testing a new combination of medications to see if it can help children and young adults with tough-to-treat blood cancers feel better and improve their chances of recovery.

Quick facts

PhasePhase1; Phase2
Study typeInterventional
Enrollment26 (estimated)
Ages1 Year to 21 Years
SexAll
SponsorPrincess Maxima Center for Pediatric Oncology Academic / other
Drugs / interventionstrametinib, CAR-T, chemotherapy, IMMUNOTHERAPY, radiation, methotrexate, cyclophosphamide
Locations36 sites (Vienna and 35 other locations)
Trial IDNCT05658640 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the safety and efficacy of trametinib combined with dexamethasone, cyclophosphamide, and cytarabine in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). It employs a biomarker-driven approach to identify patients with specific alterations in the RAS-RAF-MAPK pathway, aiming to improve treatment outcomes. The trial is part of a larger master protocol designed to evaluate multiple investigational products for pediatric hematological malignancies.

Who should consider this trial

Good fit: Ideal candidates are children and young adults aged 1 to 21 with relapsed or refractory ALL or LBL and specific genetic alterations.

Not a fit: Patients without actionable alterations in the RAS-RAF-MAPK pathway or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a more effective therapy option for children with difficult-to-treat blood cancers.

How similar studies have performed: Other studies have shown promise with similar biomarker-driven approaches in treating pediatric hematological malignancies, suggesting potential for success in this trial.

Eligibility criteria

Show full inclusion / exclusion 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.

Where this trial is running

Vienna and 35 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Acute Lymphoblastic Leukemia, in RelapseLymphoblastic Lymphoma RecurrentLymphoblastic Lymphoma RefractoryAcute lymphoblastic leukemiaLymphoblastic lymphomaBiomarker driven clinical trialTrametinibChemotherapy
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.