PEPN2312: A Pediatric Early Phase Clinical Trials Network (PEP-CTN) Phase 1 Trial of Imetelstat with Fludarabine/Cytarabine in Pediatric Patients with Relapsed/Refractory AML, MDS, or JMML
Authors: Stevens Alexandra McLean , O'Brien Maureen M. , Liu Xiaowei , Minard Charles G , Militano Olga , Reid Joel M , Navada Shyamala , Cooper Todd M , Tasian Sarah K. , Fox Elizabeth , Weigel Brenda J. 
Published: December 2024

Introduction:
Survival of children with relapsed/refractory (r/r) acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) remains dismal, and successful treatment approaches are limited. Myeloid leukemias frequently have high telomerase expression, and neoplastic progenitor cells have relatively shorter telomeres compared to normal tissues due to the balance between frequent malignant cell division and compensatory increased telomerase activity. In one study, the 5-year overall survival (OS) in children with AML and lower telomerase activity was 88% compared to 43% for those with higher activity, suggesting potential prognostic and therapeutic importance of telomerase in this population (Verstovsek Cancer 2003).
Imetelstat is a first-in-class telomerase inhibitor approved by the FDA in 2024 for the treatment of adult patients with low-to-intermediate-1 risk myelodysplastic syndromes (LR-MDS) with transfusion-dependent anemia who are r/r/ineligible for erythropoiesis-stimulating agents. . Imetelstat has also been shown to drive AML cells into ferroptosis (Bruedigam Nature Cancer 2024). The Children's Oncology Group (COG) previously conducted the ADVL1112 Phase 1 study of imetelstat monotherapy in children with r/r solid tumors or lymphomas (Thompson CCR 2013). Imetelstat was administered intravenously on Days 1 and 8 of a 21-day cycle. The recommended phase 2 dose (RP2D) was 268 mg/m2. Imetelstat was well-tolerated with no grade &gt;3 non-hematologic toxicities and one dose-limiting thrombocytopenia observed in a subject treated at the RP2D. In preclinical studies, imetelstat was active against leukemia stem cells in pediatric AML patient derived xenograft models (Barwe J Clin Med, 2022).
Methods:
PEPN2312 is an open-label, multi-center phase 1 study of imetelstat in combination with fludarabine/high dose cytarabine (FLA) for patients with AML in second or greater relapse, refractory to re-induction after first relapse, or r/r MDS or JMML (NCT06247787). The primary objective of this study is to estimate the maximum tolerated dose (MTD) and/or RP2D of imetelstat in combination with FLA in this patient population. Secondary objectives include toxicity assessment, pharmacokinetics, clinical response/minimal residual disease assessments per standard criteria, and OS. Exploratory analyses will be conducted to analyze telomerase activity in peripheral blood mononuclear cells, conduct pharmacodynamic studies, and evaluate any changes in cytogenetic and mutational abnormalities. Eligible patients must be between the ages of 1 to 18 at the time of study enrollment with Lansky/Karnofsky performance status of ≥50. Patients with leukemia must have platelet count &gt;25,000/µL and hemoglobin &gt;8 g/dL (transfusions allowed). Patients known to have a congenital bone marrow failure syndrome are excluded.
This study will use the Rolling 6 design to estimate the MTD/RP2D. The starting dose of imetelstat (DL1) is 212 mg/m2 IV over 2 hours (80% of the single-agent RP2D) given on days 1 and 8 of a 28-day cycle in combination with FLA administered days 2-6. Premedication for infusion reactions with an antihistamine and corticosteroid are required prior to each dose of imetelstat. Patients may receive up to 2 cycles of therapy in the absence of progressive disease or unacceptable toxicity as graded by CTCAE version 5.0. Response assessment will be performed via morphology and central flow cytometry analysis for patients with AML and standard response criteria for patients with JMML or MDS (Niemeyer Haematologica 2015; Zeidan Blood 2023). One dose escalation to 268 mg/m2 (DL2) will be explored if DL1 is deemed safe. Intra-patient dose escalation is not permitted. Pharmacokinetic sampling will be performed during cycle 1. Once the MTD/RP2D is determined, further assessment of safety and preliminary activity of imetelstat and FLA chemotherapy will occur in an expansion cohort of up to 6 additional patients treated at the MTD/RP2D. PEPN2312 was activated in July 2024 and will enroll at 21 participating COG/PEP-CTN sites.