Liu, Xiaowei

Abstract Purpose: Selinexor is a first-in-class, central nervous system (CNS)–penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase I trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880). Patients and Methods: A rolling six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics of selinexor administered once (35–45 mg/m2) or twice (20–35 mg/m2) weekly during a 28-day cycle (part A). Ten additional patients with high-grade glioma (HGG) were treated at the MTD administered once weekly (part B). Results: In part A, 49 patients were enrolled. Continuous twice weekly dosing was limited by extended hematologic toxicity. The MTD on a twice weekly schedule for 3 weeks on/1 week off (twice weekly 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and aspartate aminotransferase/alanine aminotransferase increase. On a continuous once weekly schedule, the MTD was 35 mg/m2/dose; DLTs included seizure and thrombocytopenia. In part B (HGG expansion), there were no additional DLTs observed. Non-DLTs included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range, 1–9); eight of 59 patients (13.5%) received 5 to 9 cycles, five of whom had HGG. Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic, requiring dose or dose-frequency reduction. The MTD and recommended initial phase II dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose once weekly.

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.

10015 Background: The Children’s Oncology Group developed and implemented a unified method of dosing anticancer drugs in infants and small children with a BSA < 0.6 m2. The dosing tables use BSA-based dose banding and account for deliverable doses/volumes of the drugs. We studied the PK of VCR (1.5 mg/m2 dose level) in infants and children to determine whether this new infant dosing method achieves uniform drug exposures across the pediatric age span. Methods: We designed a sampling strategy to limit the blood volume required by focusing on the elimination (β) phase of the VCR concentration-time curve, which accounts for > 80% of the total area-under the curve (AUC). Duplicate samples to detect contamination were drawn at 3 post-infusion time points (2, 6-8 and 18-24 hr) through a central venous catheter (CVC) after a 90 min flush. VCR concentrations were measured at the Children’s Hospital of Philadelphia using a validated high-pressure liquid chromatography/tandem mass spectrometry method with a lower limit of quantitation (LLQ) of 0.25 ng/mL. A one-compartment model was fit to the concentration-time data using population PK methods (Phoenix NLME). The AUCβ was derived from the dose and clearance for each patient. Patients were accrued in 4 age groups (≤6 mo, goal n = 20); > 6 mo to ≤12 mo, goal n = 10; > 12 mo to ≤36 mo, goal n = 10; and > 36 mo to ≤12 yr, goal n = 10) to focus on infants and ensure representation across the pediatric age range. Results: 52 eligible patients have been enrolled and 39 are evaluable for PK analysis, including 9 ≤6 mo, 8 > 6 mo and ≤12 mo, 12 > 12 mo and ≤36 mo, and 10 > 36 mo and ≤12 y,. The median (range) age is 13.5 mo (1.15-112 mo). VCR was quantifiable in all samples, and there was no evidence of contamination in the duplicate samples drawn through the CVC. The mean ± SD AUCβ in the 39 evaluable patients was 54.7 ± 19.8 ng⋅h/mL. As shown in the Table, the AUCβ is similar in patients with a BSA < 0.6 m2 dosed according to the BSA-banded infant dosing table and patients with a BSA ≥0.6 m2 dosed by multiplying their BSA times 1.5 mg/m2 (p = 0.53, Mann Whitney test). Conclusions: The VCR BSA-banded infant dosing table appears to provide uniform VCR exposure for infants and young children compared to conventional BSA-based dosing in older children. The study design and sampling strategy facilitated rapid accrual of a young population and generated more VCR PK data in infants within a year than has been published since the drug was approved in 1963. This study demonstrates the feasibility of systematically studying other anticancer drugs in infants and other special populations to ensure they are receiving safe and effective doses. VCR AUCβ by dosing method. Clinical trial information: NCT05359237 . [Table: see text]

Abstract Purpose: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. Patients and Methods: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. Results: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. Conclusions: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.