1. Nalley, Catlin

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A Phase I trial of selinexor in children and adolescents with recurrent central nervous system (CNS) and solid tumors, including lymphoma, found that treatment-related toxicities were primarily hematological and gastrointestinal, according to data presented during the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics (Abstract P162).

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The study authors identified the maximum tolerated dose (MTD) of selinexor for this patient population is 20 mg/m2/dose twice weekly for 3 weeks followed by 1 week off. They reported that, on a continuous once weekly schedule, the MTD and recommended Phase II starting dose of this agent is 35 mg/m2/dose.


Selinexor is an oral, first-in-class inhibitor of nuclear export, according to study author Adam L. Green, MD, a pediatric oncologist at the University of Colorado School of Medicine, Aurora, who explained that it functions by "binding to the nuclear export protein XPO1, and thus preventing export from the nucleus of key tumor suppressor proteins and restoring their function in the nucleus."


Currently, selinexor is FDA-approved for refractory multiple myeloma and diffuse large B-cell lymphoma in adult patients. "It has strong preclinical evidence in multiple pediatric brain and solid tumors," noted Green. "It was previously evaluated in two Phase I trials for pediatric leukemia."


Methods, Findings

During the conference, Green presented dose-escalation results from a Phase I trial examining the use of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma. The primary aims of the study included determining the recommended Phase II dose, characterizing toxicity, and measuring pharmacokinetics.


The researchers used a rolling six design to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Eligible patients were 12-21 years old and, due to the pill size and a need to swallow intact tablets, only patients with a body surface area of at least 0.84m2 were enrolled, according to Green.


Other eligibility requirements were recurrent/refractory CNS and solid tumors, including lymphoma; BMI greater or equal to the third percentile; no known macular degeneration, uncontrolled glaucoma, or cataracts; no Grade 3 ataxia or grade >1 extrapyramidal movement disorder; and adequate organ function.


"We have enrolled 43 patients in this phase of the study, with a male to female ratio of 17 to 26," said Green. "The median age of our patients was 15 years, and the median number of prior treatment regimens was three. We enrolled 16 patients with extracranial solid tumors, the most common which was osteosarcoma, and 27 patients with CNS tumors, the most common of which was glioblastoma and other high-grade gliomas."


At the starting dose (35 mg/m2/dose, twice weekly), no dose-limiting toxicities were observed. However, two subjects had unexpected late myelosuppression, delaying initiation of Cycle 2, according to the study authors. They adjusted the dosing schedule to twice weekly for 3 weeks followed by a 1-week break, according to Green.


At this dose level, Green reported four dose-limiting toxicities out of 12 evaluable patients. Therefore, they de-escalated to 20 mg/m2/dose twice weekly and observed one dose-limiting toxicity. As a result, they identified this as the recommended Phase II dose for that schedule


"Because of concern with that dose level and its ability to give adequate intratumoral PK in brain tumors and also pharmacokinetic results from adults, as well as evidence that selinexor may be better tolerated and just as efficacious at weekly dosing, we then investigated a weekly dosing schedule," Green explained.


At the initial dose level (45 mg/m2 weekly), two of six patients had dose-limiting toxicities. This included prolonged Grade 2 thrombocytopenia or Grade 3 seizure in a primary CNS tumor patient. Following de-escalation, six patients were administered 35 mg/m2/dose once weekly. One dose-limiting toxicity of Grade 3 thrombocytopenia occurred. This was declared the recommended Phase II dose for weekly dosing, Green reported.


When discussing the pharmacokinetic results for the twice-weekly dosing schedule, Green noted that these values compared favorably to adult pharmacokinetics at the same dose levels, and the Cmax and AUC appear to be proportional to the dosing.


"In terms of toxicities and outcomes, we had several patients with hematologic toxicities, the most common of which was neutropenia," noted Green. "We also had GI toxicity in terms of nausea, fatigue, and anorexia as well as vomiting. [There was] some neurologic toxicity as well, including one patient with a brain tumor who had a first-time seizure."


The imaging analysis is ongoing for responses, Green noted. At the data cutoff of March 31, 2021, the median number of cycles received was one (range 1-9). Thirteen out of the 43 patients received 2-3 cycles while six received 5-9 cycles.


"In conclusion, the selinexor-related toxicities that we observed were primarily reversible gastrointestinal and hematological events," Green summarized. "The maximum tolerated dose in our patient population with recurrent solid and CNS tumors was 20 mg/m2/dose twice weekly for 3 weeks followed by 1 week off. The recommended Phase II dose for future trials is 35 mg/m2/dose on a continuous once weekly schedule."


Catlin Nalley is a contributing writer.