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Current Research Studies

Risk stratified treatment for patients with newly diagnosed juvenile myelomonocytic leukemia: A Phase I/II non-randomized study of trametinib and azacitidine with or without chemotherapy (IND # 164058)

T2020-004

  • Condition(s): Leukemia, other, Myeloid and Monocytic Leukemia
  • Phase: I/II
  • Clinicaltrials.gov ID: NCT05849662

What is the goal of the study?

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11 and CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event free survival after transplant is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as being predictive of outcome in JMML. In this trial, we propose that lower-risk patients are defined those with 1 somatic alteration AND low DNA methylation while high-risk patients are defined as those with more than 1 somatic alteration OR intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 which is downstream of Ras/MAPK signaling. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with a BRAF V600E or V600K mutation. It is currently being investigated in an ongoing phase 2 clinical trial for patients with relapsed or refractory JMML. Four of nine patients enrolled on that trial had an objective response. Azacitidine was recently tested in a phase 2 clinical trial for newly diagnosed JMML patients. Eighteen patients enrolled and after 3 courses of azacitidine monotherapy, 11/18 patients achieved an objective response, 17 patients proceeded to HSCT and 82% were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine is now FDA approved for patients with newly diagnosed JMML. This clinical trial will risk stratify patients based on DNA methylation and mutational burden to receive different therapies. Lower-risk patients will receive trametinib and azacitidine for up to 12 courses and will only proceed to HSCT in the event of progressive disease. High-risk patients will receive trametinib and azacitidine in combination with cytarabine and fludarabine for up to two courses and then will proceed to off-protocol HSCT. We will collect sequential samples from all patients who consent to optional studies to better understand JMML. This trial will provide an opportunity to interrogate the genetic, biochemical, and functional perturbations of response and resistance to trametinib and azacitidine in patients with JMML. The primary objectives of this study are to determine the safety of combining trametinib with azacitidine (Aza) for patients with newly diagnosed lower-risk JMML and to determine the safety of combining trametinib with azacitidine, fludarabine (FLA) and cytarabine for patients with newly diagnosed high-risk JMML. Secondary objectives are to describe the event free survival (EFS) in patients with newly diagnosed lower-risk JMML treated with trametinib and azacitidine who do not proceed to stem cell transplant within 1 year and to determine the rate of molecular response pre-transplant using trametinib plus Aza-FLA in patients with newly diagnosed high-risk JMML.

Who can participate in the study?

Please contact the study team listed below to learn more.

Study Team: