Fox, Elizabeth

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 >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 >25,000/µL and hemoglobin >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.

Abstract Background This is a phase II subprotocol of the NCI-COG Pediatric MATCH study evaluating vemurafenib, a selective oral inhibitor of BRAF V600 mutated kinase, in patients with relapsed or refractory solid tumors harboring BRAF V600 mutations. Methods Patients received vemurafenib at 550 mg/m2 (maximum 960 mg/dose) orally twice daily for 28-day cycles until progression or intolerable toxicity. The primary aim was to determine the objective response rate and secondary objectives included estimating progression-free survival and assessing the tolerability of vemurafenib. Results Twenty-two patients matched to the subprotocol and 4 patients (18%) enrolled. Primary reasons for non-enrollment were ineligibility due to exclusions of low-grade glioma (n = 7) and prior BRAF inhibitor therapy (n = 7). Enrolled diagnoses were one each of histiocytosis, ameloblastoma, Ewing sarcoma, and high-grade glioma, all with BRAF V600E mutations. Treatment was overall tolerable with mostly expected grade 1/2 adverse events (AE). Grade 3 or 4 AE on treatment were acute kidney injury, hyperglycemia, and maculopapular rash. One patient came off therapy due to AE. One patient (glioma) had an objective partial response and remained on protocol therapy for 15 cycles. Conclusion There was a low accrual rate on this MATCH subprotocol, with only 18% of those who matched with BRAFV600 mutations enrolling, resulting in early termination, and limiting study results (ClinicalTrials.gov Identifier: NCT03220035).