Risk Stratified Treatment for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase 1/2 Non-Randomized Study of Trametinib and Azacitidine with or without Chemotherapy

Background: 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, or CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event-free survival of children with JMML after HSCT is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as predictive of clinical outcomes in patients with JMML. In the T2020-004 phase 1/2 clinical trial, we will define lower-risk patients as those with one somatic alteration and low DNA methylation and high-risk patients as those with more than one somatic alteration or intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 in the Ras/MAPK signaling pathway. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAF V600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib. Clinical investigation of trametinib monotherapy via the Children’s Oncology Group ADVL1521 phase 2 trial (NCT03190915) showed efficacy in children with relapsed/refractory JMML. Phase 2 clinical trial evaluation of azacitidine in children with newly-diagnosed JMML was also efficacious and led to its FDA approval. In this trial, trametinib will be tested in combination with azacitidine in lower-risk patients and in combination with azacitidine and chemotherapy for high-risk patients.

Study Design and Methods: This is a non-randomized, risk stratified, Phase 1/2 study for patients with newly-diagnosed JMML (NCT05849662) conducted via the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium with safety and efficacy phases for both lower-risk and high-risk cohorts. Lower-risk patients will receive trametinib once-daily for 28 days in combination with azacitidine administered daily for five days per cycle. Lower-risk patients can receive up to 12 cycles and will proceed to HSCT only if they experience progressive disease or relapse. High-risk patients will receive trametinib administered once-daily for 28 days in combination with azacitidine, fludarabine, and cytarabine (aza/FLA) administered daily for five days per cycle. High-risk patients will receive up to two cycles of therapy before proceeding to HSCT off protocol.

Key Eligibility: Patients aged 1 month to 21 years who meet World Health Organization criteria for JMML will be eligible.

Objectives: The primary safety objectives are to determine the safety of combining trametinib with azacitidine for lower-risk patients and combining trametinib with aza/FLA for high-risk patients. The secondary efficacy objectives are to determine the event-free survival for lower-risk patients in the absence of HSCT and the molecular response rates pre-HSCT for high-risk patients.

Sample Size and Statistical Design: A rolling 6 trial design will be used during Phase 1 of the study to determine the recommended phase II dose (RP2D) of trametinib for lower-risk and high-risk patients in combination with their respective therapies. Starting trametinib dose is 0.032mg/kg daily if less than 6 years of age, or 0.025mg/kg daily if 6 years or older, with one dose level de-escalation if indicated. Phase II of the study involves lower-risk and high-risk cohort expansions at the RP2D of trametinib. Target accrual is 22 patients in the lower-risk arm and 42 patients in the high-risk arm. The study is open to accrual at all TACL consortium sites.

We acknowledge the TACL Consortium’s scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Novartis Pharmaceuticals Corporation provided the investigative drug in support of this trial. This study is supported by the National Institute of Health, National Cancer Institute (R37CA266550), the Pediatric Cancer Research Foundation, and the Cannonball Kids Cancer Foundation.