Phase 1 trial of selinexor in pediatric recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium Trial

Abstract

Background:

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 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880).

Methods:

A rolling-six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics (PK) of selinexor administered once (QW, 35–45 mg/m²) or twice (BIW, 20–35 mg/m²) weekly during a 28-day cycle (Part A). Ten additional patients with high-grade glioma (HGG) were treated at the QW MTD (Part B).

Results:

In Part A, 49 patients were enrolled. Continuous BIW dosing was limited by extended hematologic toxicity. The MTD on a BIW schedule for three weeks on/one-week off (BIW 3/1) was 20 mg/m²/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and AST/ALT increase. On a continuous QW 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-dose-limiting toxicity 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 5–9 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 2 dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m²/dose QW.

Introduction

Selinexor is orally bioavailable, CNS penetrant,¹ and has shown preclinical efficacy in multiple pediatric cancer models, including HGG,¹ as well as other CNS and extracranial solid tumors.² Selinexor binds and inactivates XPO1 (Exportin 1, CRM1), the primary nuclear exporter of many key tumor suppressor and growth regulatory proteins (TSP/GRP), including TP53, CDKN1A, CDKN1B, RB1, FOXO, and NFKBIA.³ This exporter is overexpressed in many cancer types, and overexpression is associated with poor outcomes.⁴ Active nuclear export of TSP/GRP is an efficient and rapid means of overcoming normal cell cycle regulation and the genomic stability assessment in cancer cells.⁵ Unlike earlier irreversible inhibitors of XPO1, which had severe toxicity,⁶ selinexor binds and inactivates XPO1 in a slowly reversible manner, forcing the nuclear retention of key TSP/GRP, and activating cell cycle checkpoints and genomic surveillance.⁵ In malignant cells, this leads to apoptosis, whereas normal cells undergo transient cell cycle arrest and subsequent recovery when the export block is released.^7,8 This mechanism supports selinexor dosing weekly or twice weekly despite a short half-life of 6–8 hours.^9,10

Selinexor received accelerated FDA approval for adults with relapsed/refractory multiple myeloma¹¹ in combination with dexamethasone, and for relapsed/refractory diffuse large B-cell lymphoma as a single agent.¹² In a phase 2 study in adults with recurrent glioblastoma (GBM), selinexor (80 mg QW) resulted in a 10% overall response rate (ORR) and a 30% 6-month progression-free survival (PFS) rate.¹³ Two phase 1 pediatric studies of selinexor were completed in relapsed leukemia, both using a BIW schedule. In the initial study of selinexor with fludarabine and cytarabine, cerebellar toxicity was dose-limiting, and the recommended phase 2 dose (RP2D) was 55 mg/m² BIW; 7/15 patients demonstrated a complete response (CR).¹⁴ The second trial evaluated single agent selinexor and established the RP2D of 40 mg/m² BIW; the ORR was 12%.¹⁵

While outcomes have improved for most childhood cancers, treatment gains have been limited for a subset of children with aggressive non-hematologic malignancies, notably sarcoma and brain tumors. Based on its preclinical and early clinical effectiveness, we conducted a phase 1 study of selinexor in children with recurrent or refractory CNS and extracranial solid tumors. Dosing levels were chosen based on the prior pediatric trials and limited by available tablet sizes. The primary objectives were to estimate the MTD and/or RP2D of selinexor, and to characterize the toxicities and first dose PK of selinexor in this pediatric population.

Patients and Methods

Patients

Eligible patients were between 1–21 years with recurrent/refractory solid tumor, including lymphoma and CNS tumors (Part A), or recurrent/refractory HGG not requiring surgical resection (Part B). Other eligibility criteria included Karnofsky/Lansky performance score ≥ 50%, and if currently required, a stable or decreasing corticosteroid dose. Patients were required to have a body mass index (BMI) ≥ third percentile, no Grade ≥ 3 ataxia or Grade ≥ 2 extrapyramidal movement disorder, and no macular degeneration, uncontrolled glaucoma, or cataracts. There was no limit on prior treatment regimens. Hematologic criteria included an ANC ≥ 1,000 cells/uL, transfusion-independent platelet count ≥ 100,000 × 10⁹/L, and baseline hemoglobin ≥ 8 g/dL. Standard organ function was required (Supplemental Table 1).

The study was approved by the National Cancer Institute (NCI) Pediatric Central Institutional Review Board and conducted in accordance with good clinical practices and the Declaration of Helsinki. Informed written consent, and assent as appropriate per institutional guidelines, was obtained from subjects and their guardians prior to enrollment. The trial was listed on clinicaltrials.gov (NCT02323880).

Treatment Plan

Selinexor (Xpovio^™, KPT-330) was supplied by Karyopharm Therapeutics (Newton, MA) in 10 or 25 mg tablets for oral administration and administered with food in 28-day cycles (see Supplemental Table 2 for dosing nomograms). Three schedules were studied: twice weekly on a continuous schedule (BIW); twice weekly with 3 weeks on and 1 week off (BIW 3/1); and a once weekly continuous schedule (QW).

For Part A, the starting dose of selinexor was 35/mg/m² BIW, continuously (DL1*). Dose escalations to 45 mg/m² and 65 mg/m² were planned with a possible dose de-escalation to 20 mg/m². A rolling-six design was used for dose escalation. The MTD was defined as the maximum dose at which fewer than one-third of patients experienced DLT during cycle 1 of therapy. Once the MTD or RP2D was defined, up to six additional patients were to be included in a PK expansion cohort to acquire additional PK data in at least 6 subjects under 12 years of age. Part B was designed to enroll patients with recurrent/ progressive HGG not requiring surgical resection to be treated at the MTD on the schedule with the highest mean maximum concentration (C_max) as determined in Part A.

Toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Non-hematologic DLT was defined as any grade ≥3 toxicity at least possibly attributable to selinexor, excluding grade 3 anorexia or weight changes; nausea, vomiting, or dehydration resolving within 3 days; grade 3 liver transaminase or bilirubin elevation resolving within 7 days; grade 3 diarrhea resolving within 7 days; grade 3 infection < 5 days; and grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to supplementation. In addition, any non-hematologic toxicity that lasted ≥ 7 days and required omission of 2 doses in a cycle was considered a DLT. Hematologic DLT was defined separately as: grade ≥4 neutropenia, thrombocytopenia, or anemia not due to malignant infiltration; grade 3 thrombocytopenia persisting for ≥ 7 days, requiring a platelet transfusion on 2 separate days within a 7-day period, or associated with clinically significant bleeding, petechiae, or purpura; and myelosuppression causing a delay of > 14 days between treatment cycles. Upon meeting eligibility parameters, patients experiencing DLT could remain on protocol therapy with one dose-level reduction; patients with a first episode of grade 4 neutropenia recovering to grade ≤ 2 or within 7 days, were able to continue at the same dose.

Response Criteria

Radiographic response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) for subjects with solid tumors and modified Response Assessment in Neuro-Oncology (RANO) for subjects with CNS tumors. Tumor disease evaluations were performed at the end of cycles 1, 3, and 5, and every 3 cycles thereafter. Objective responses required two consecutive 2D measurements on standard imaging done 4 weeks apart. Partial or complete responses and prolonged stable disease (≥ 6 cycles) required central review.

Pharmacokinetic Studies

Blood samples were drawn for PK prior to and at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours following the first dose. Collection tubes were immediately mixed by inversion 8–10 times then placed on ice or at 4°C. Blood was centrifuged at 2000g for 10 minutes at 4°C within 30 minutes of collection. The plasma layer was carefully transferred and divided into 2 LoBind^™ Eppendorf tubes. Plasma samples were immediately frozen and stored in a −80°C freezer until shipping for analysis. Selinexor plasma concentrations were determined with a validated liquid chromatography-tandem mass spectrometry (AIT Bioscience LLC) method meeting the criteria of the FDA and European Medicines Agency guidelines on Bioanalytical Method Validation. The intra- and inter-day precision was determined at 4 concentrations (1, 3, 75 and 750 ng/ml) with the coefficient of variation (CV%) less than 6% (range 1.7–5.5% and 1.5–5.1% respectively). The same concentrations were used for intra and inter-day accuracy with the %CV less than 9% (range 6.9–8.3% and −0.2–2.7%, respectively) The linear range was 1–1,000 ng/ml and the limit of quantitation (LOQ) was 1.0 ng/ml. Noncompartmental analyses were performed using standard methods with the Phoenix software v8.4 (Certara USA Inc, Princeton, NJ, RRID:SCR_024504).

Pharmacodynamic Studies

Blood samples for PD studies were drawn prior to and 4 hours after the first dose. Blood was collected in PAXgene Blood RNA Tubes (cat. no. 762165) in 2.5 mL aliquots, processed on-site according to the manufacturer instructions, and maintained at −80 C. RNA was isolated from whole blood samples using the PAXgene Blood RNA Kit (cat. no. 762164), and RNA purity verified using the NanoDrop 2000. cDNA was created using the QuantiTect Reverse Transcriptome Kit (cat. no. 205313) and measured through quantitative polymerase chain reaction (qPCR) to compare pre-dose and post-dose XPO1 expression. qPCR reactions included 1 μL of an XPO1 probe (RefSeq Hs00185645_m1) or GAPDH control probe (Hs02786624_g1), 4 μL of cDNA, 10 μL of TaqMan Universal PCR Master Mix (cat. no. 4304437), and 5 μL of RNAse-free water. Results were analyzed using Excel (Microsoft, RRID:SCR_016137) and Prism (GraphPad, RRID:SCR_002798). Pre-dose XPO1 expression values were normalized and compared to post-dose normalized values via Wilcoxon signed rank test. Expression change between dose levels was compared by Kruskal-Wallis test.

Data Availability Statement

All datasets analyzed in the study were generated by the authors and are included in the main or supplementary data except for those that would compromise patient privacy or consent. All deidentified data are available upon reasonable request of the corresponding author.

Results

Patient Characteristics

Fifty-nine patients were enrolled (Figure 1): (Part A) 37 in dose-escalation; 12 in PK/age expansion; and 10 with recurrent/progressive HGG (Part B). All patients were eligible. Baseline characteristics are presented in Table 1. Overall, the median age was 15 (range: 6–20) years; 56% patients were female; 41 patients (69%) had a primary CNS tumor; and 18 (31%) had a non-CNS solid tumor. The most common diagnoses were high-grade glioma, osteosarcoma, and ependymoma; 92% had received prior chemotherapy regimens [median of 3 (range:1–13)], and 90% had received prior radiation.

Figure 1:

Study diagram

Table 1:

Patient Characteristics for Eligible Patients (N=59)

Characteristic	Part A (N=37)	PK (N=12)	Part B (N=10)	Total (N=59)
Age
Median	15.0	11.0	15.5	15.0
Range	6.0, 20.0	6.0, 20.0	7.0, 19.0	6.0, 20.0
Gender, n (%)
Male	14 (37.8%)	5 (41.7%)	7 (70.0%)	26 (44.1%)
Female	23 (62.2%)	7 (58.3%)	3 (30.0%)	33 (55.9%)
Race, n (%)
White	24 (64.9%)	6 (50.0%)	5 (50.0%)	35 (59.3%)
Asian	2 (5.4%)	0 (0.0%)	2 (20.0%)	4 (6.8%)
Black or African American	3 (8.1%)	4 (33.3%)	1 (10.0%)	8 (13.6%)
Multiple Races	1 (2.7%)	0 (0.0%)	1 (10.0%)	2 (3.4%)
Unknown	7 (18.9%)	2 (16.7%)	1 (10.0%)	10 (16.9%)
Ethnicity, n (%)
Hispanic or Latino	6 (16.2%)	1 (8.3%)	1 (10.0%)	8 (13.6%)
Not Hispanic or Latino	28 (75.7%)	11 (91.7%)	8 (80.0%)	47 (79.7%)
Unknown	3 (8.1%)	0 (0.0%)	1 (10.0%)	4 (6.8%)
Prior Chemotherapy
N	34	10	10	54
Median regimens	3.0	3.0	2.0	3.0
Range	1.0, 10.0	1.0, 13.0	1.0, 3.0	1.0, 13.0
Prior Radiation
N	33	10	10	53
Median regimens	1.0	1.0	1.0	1.0
Range	1.0, 3.0	1.0, 2.0	1.0, 3.0	1.0, 3.0
Diagnosis, n (%)
CNS Tumors
Choroid plexus carcinoma	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Ependymoma	3 (8.1%)	2 (16.7%)	0 (0.0%)	5 (8.5%)
High-Grade Glioma	16 (43.2%)	4 (33.3%)	10 (100.0%)	30 (50.9%)
Low-Grade Glioma	2 (5.4%)	0 (0.0%)	0 (0.0%)	2 (3.4%)
Medulloblastoma	2 (5.4%)	0 (0.0%)	0 (0.0%)	2 (3.4%)
Pineoblastoma	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Non-CNS Tumors
Desmoplastic small round cell tumor	0 (0.0%)	1 (8.3%)	0 (0.0%)	1 (1.7%)
Ewing sarcoma	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Germ cell tumor, nonseminomatous	0 (0.0%)	1 (8.3%)	0 (0.0%)	1 (1.7%)
Hodgkin lymphoma	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Myxoid liposarcoma	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Nephroblastoma	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Neuroblastoma	1 (2.7%)	1 (8.3%)	0 (0.0%)	2 (3.4%)
Osteosarcoma	4 (10.8%)	2 (16.7%)	0 (0.0%)	6 (10.2%)
Sarcoma NOS	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (1.7%)
Synovial sarcoma	2 (5.4%)	1 (8.3%)	0 (0.0%)	3 (5.1%)

Toxicity

A total of 55/59 patients were evaluable for DLT determination (Table 2). Three patients were inevaluable due to not receiving the required number of selinexor doses for reasons other than toxicity, and one did not complete all required toxicity evaluations (Supplemental Table 3). At dose level 1 on the continuous dosing schedule (DL1*; 35 mg/m² BIW), no DLTs were observed in the first six patients. However, two patients experienced unexpectedly prolonged hematologic toxicity, not qualifying as a DLT. The study was amended to have a rest week during the fourth week of each 28-day cycle. At DL1 on the revised schedule [35 mg/m² twice weekly 3 weeks on/1 week off (BIW 3/1)], 2/6 of the first 6 patients experienced DLT: grade 3 ALT increase and grade 3 fatigue. The protocol allowed enrollment of an additional 6 patients if the two DLTs were of different classes and were readily reversible. Two of 6 additional patients also experienced DLT: grade 3 thrombocytopenia and grade 3 fatigue. Both patients experiencing grade 3 fatigue had CNS tumors and developed profound somnolence requiring hospitalization. Both recovered and did not have symptom recurrence after restarting selinexor on a QW schedule. With 4/12 patients experiencing DLTs, the dose was de-escalated to 20 mg/m² BIW 3/1. At this dose, 1/6 patients experienced DLT (grade 3 AST/ALT increase), and the MTD on this schedule was declared as 20 mg/m². Two of 6 patients subsequently enrolled on the PK expansion cohort (BIW 3/1) developed DLTs: one with grade 3 acute neurologic change, involving reversible cerebellar dysfunction, and one with grade 4 neutropenia. Overall, 3/12 (25%) subjects experienced cycle 1 DLT at the BIW 3/1 MTD.

Table 2:

Dose Escalation and DLT Summary

Dose Level	Selinexor Dose	Schedule (4 week cycles)	Part	Number of Patients Entered	Number of Patients Evaluable	Number of Patients Inevaluable	Number of Patients with Cycle 1 DLT	Cycle 1 DLTs Observed	Number of Patients with Later-Cycle DLTs
DL 1*	35 mg/m2	Twice weekly continuously	Part A	6	6	0	0		1
DL 1	35 mg/m2 (DL 1)	Twice weekly weeks 1–3	Part A	13	12	1	4	Fatigue (2), ALT increase, platelet decrease	1
DL -1	20 mg/m2 (DL -1)	Twice weekly weeks 1–3	Part A	6	6	0	1	ALT/AST increase	.
DL -1	20 mg/m2 (DL -1)	Twice weekly weeks 1–3	PK	6	6	0	2	Acute neurologic change, neutropenia	1
WDL 1	45 mg/m2 (Weekly Dose Level (WDL) 1)	Weekly continuously	Part A	6	6	0	2	Platelet decrease, seizure	.
WDL -1	35 mg/m2 (WDL-1)	Weekly continuously	Part A	6	6	0	1	Platelet decrease	.
WDL -1	35 mg/m2 (WDL-1)	Weekly continuously	PK	6	6	0	0		.
WDL -1	35 mg/m2 (WDL-1)	Weekly continuously	Part B	10	7	3	0		.

^*Although there were no DLTs, the schedule was changed after this dose level from continuous dosing each week to dosing only weeks 1–3 of each cycle due to unexpected hematopoietic toxicity.

Based on data from selinexor trials in adults demonstrating improved tolerability and equivalent efficacy of QW dosing (See Discussion), as well as interim PK analysis suggesting C_max at the BIW 3/1 MTD may not be sufficient to achieve adequate CNS concentrations, the study was amended to evaluate QW dosing. At weekly dose level 1 (WDL1, 45 mg/m²/dose), 2/6 patients experienced DLT (prolonged grade 2 neutropenia, and grade 3 seizure). The dose was de-escalated to 35 mg/m² (WDL −1) and only 1/6 patients experienced DLT (grade 3 thrombocytopenia); 35 mg/m² was thus declared the MTD on the QW schedule and the overall initial RP2D. No additional cycle 1 DLTs were observed in six evaluable subjects in the PK expansion (WDL −1, 35 mg/m² QW) and seven evaluable HGG subjects (Part B). Three patients experienced DLTs in later cycles, including neutropenia, elevated lipase, and acute neurologic changes (one each at DL1 (BIW 3/1), WDL1, and WDL −1). Non-dose-limiting cycle 1 toxicities of grade 2 and above occurring in >10% of subjects included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. A full assessment of cycle 1 and cycle 2+ non-dose-limiting toxicities is listed in Table 3 and Supplemental Tables 4-7.

Table 3:

Non-Dose Limiting Toxicities Observed in >10% of Evaluable Patients in Cycle 1, for All Dose Levels and RP2D

Toxicity Class	Toxicity	All Dose Levels (N=55)		35 mg/m2 QW (n=19)
Toxicity Class	Toxicity	All n (%)	≥ Grade 3 n (%)	All n (%)	≥ Grade 3 n (%)
Hematologic	Leukopenia	50 (91)	9 (16)	17 (89)	4 (21)
	Neutropenia	46 (84)	21 (38)	16 (84)	6 (32)
	Thrombocytopenia	32 (58)	3 (5)	8 (42)	1 (5)
	Anemia	26 (47)	-	9 (47)	-
	Lymphopenia	23 (42)	8 (15)	9 (47)	4 (21)
Gastrointestinal	Nausea	40 (73)	2 (4)	16 (84)	-
	Vomiting	35 (64)	3 (5)	13 (68)	-
	Anorexia	25 (45)	2 (4)	8 (42)	-
	Diarrhea	18 (33)	-	6 (32)	-
	Weight loss	13 (24)	-	2 (11)	-
	Constipation	10 (18)	-	3 (16)	-
Other	Fatigue	31 (56)	3 (5)	10 (53)	1 (5)
	Headache	13 (24)	-	5 (26)	-
	Dizziness	10 (18)	-	5 (26)	-
	Pain in extremity	10 (18)	-	3 (16)	-
	Hypertension	9 (16)	1 (2)	3 (16)	1 (5)
	Blurred vision	8 (15)	1 (2)	3 (16)	1 (5)
	Fever	8 (15)	-	1 (5)	-
	Sinus tachycardia	8 (15)	-	2 (11)	-
	Cough	7 (13)	-	2 (11)	-
	Arthralgia	6 (11)	-	2 (11)	-
	Back pain	6 (11)	-	2 (11)	-
	Nasal congestion	6 (11)	-	1 (5)	-
	Pruritus	6 (11)	-	1 (5)	-
Lab	Hypophosphatemia	19 (35)	2 (4)	5 (26)	-
	Elevated ALT	16 (29)	2 (4)	4 (21)	-
	Hypocalcemia	16 (29)	-	6 (32)	-
	Hyperglycemia	15 (27)	1 (2)	6 (32)	-
	Hyponatremia	15 (27)	-	5 (26)	-
	Hypokalemia	12 (22)	-	4 (21)	-
	Elevated AST	10 (18)	1 (2)	1 (5)	-
	Hypermagnesemia	10 (18)	-	5 (26)	-
	Creatinine increased	8 (15)	-	3 (16)	-

Response

The median number of cycles received was 1 (range 1–9). Eighteen of 59 patients (30.5%) received 2–3 cycles, while 8 of 59 (13.5%) received 5–9 cycles; 5 with HGG (H3K27-wild type unilateral thalamic tumor, H3K27M-mutant pontine diffuse midline glioma, anaplastic pilocytic astrocytoma, diffuse hemispheric glioma, and anaplastic pleomorphic xanthoastrocytoma); and 1 each with low-grade glioma (pilocytic astrocytoma), neuroblastoma, and Hodgkin lymphoma (Table 4). These 8 subjects had a best response of stable disease (SD) by study chair assessment, were distributed across the dosing levels/ schedules studied, and were centrally reviewed (Supplemental Table 8). There were no partial (PR) or complete responses (CR) observed.

Table 4:

Imaging Responses by Tumor Type

Tumor Type	Response
CNS	PD (1 cycle)	PD (2–3 cycles)	SD (5–9 cycles)	Inevaluable
Choroid Plexus Carcinoma				1
Ependymoma	1	3		1
High-Grade Glioma	14	8	5	3
Low-Grade Glioma	1		1
Medulloblastoma	1			1
Pineoblastoma				1
Non-CNS
DSRCT		1
Ewing Sarcoma				1
Germ Cell Tumor		1
Hodgkin Lymphoma			1
Myxoid Liposarcoma	1
Nephroblastoma		1
Neuroblastoma	1		1
Osteosarcoma	4	1		1
Sarcoma NOS	1
Synovial Sarcoma	1	1		1

CNS, central nervous system; PD, progressive disease; SD, stable disease; DSRCT, desmoplastic small round cell tumor; NOS, not overwise specified

Pharmacokinetic and Pharmacodynamic Studies

A total of 57 patients were evaluable for day 1 selinexor PK; 31 were treated with selinexor twice weekly; 26 were treated with selinexor once weekly. The concentration-time curves are shown in Figure 2. The mean (± SD) parameter estimates are summarized in Table 5 and Supplemental Table 9. One patient at 35 mg/m² QW had a concentration time profile that was not evaluable for elimination kinetics. Peak plasma concentrations (on Day 1 were achieved 3.4 ± 3.4 hours after drug administration, and the mean half-life was 7.4 ± 3.0 hours. The selinexor AUC_0–24 and C_max increased linearly in proportion to dose over the 20 – 45 mg/m² dose range. The BSA corrected oral clearance and apparent volume of distribution values were 6.9 ± 2.0 L/hr/m² and 72.3 ± 35.8 L/m², respectively. Patients <12y had a lower clearance of 6.1 ± 1.1 L/hr/m² vs 7.3 ± 2.2 L/hr/m² for patients ≥12 (p<0.001, Wilcoxon Rank Sum Test). Patients experiencing DLT had lower BSA-corrected clearance (5.9 ± 1.4, n=10) compared to those without DLT (7.1 ± 2.0, n=46), but the difference was not statistically significant (p=0.052 Wilcoxon Rank Sum Test). Within each dose level, AUC_0–24 and C_max values trended higher for patients experiencing DLT, but the differences were not statistically significant (p>0.10; Supplemental Figure 1).

Figure 2:

First day summary of concentration vs. time for all subjects (gray) with averages for patients at 20 (red), 35 (black), and 45 (blue) mg/m² dose levels.

Table 5:

Selinexor First-Dose Pharmacokinetic Data

Dose	Schedulea	N	Tmax (hrs)	Cmax (ng/mL)	Half-life (hrs)	AUC0–24h (hrs•ng/mL)	CL/F (L/hr/m2)	V/F (L/m2)
20 mg/m2	DL -1	12	3.6±1.5	324±116	7.2±1.2	2774±815	7.0±1.6	73.1±22.9
35 mg/m2	DL 1*, DL 1 and WDL -1	41	3.4±3.9	599±254	7.5±3.4c	4885±1476	6.9±2.1	73.3±39.9
45 mg/m2	WDL 1	4	3.5±1.7	755±238	6.0±1.7	6195±1593	6.9±1.5	59.2±23.0

^aSchedule (DL1*: BIW continuously; DL 1 and DL -1: BIW weeks 1–3; WDL 1 and WDL -1: QW continuously)

Thirteen paired blood samples drawn pre and 4 hours post the first dose of selinexor were analyzed for changes in XPO1 expression. XPO1 expression increased significantly overall after selinexor administration, with a median expression fold change of 4.6 (range 0.2–7.4, p=0.0005 on Wilcoxon signed rank test, Figure 3). There was no statistically significant difference in expression change between dose levels. When we looked for correlation between PK and PD measures, we found no statistically significant correlation between AUC and XPO1 expression change.

Figure 3:

Selinexor treatment increases XPO1 expression compared to pre-treatment levels at all dose levels (p<0.0001 overall by paired t-test). Diamonds indicate mean fold change for each dose level, boxes indicate interquartile range, midline of boxes indicates median, and whiskers indicate total range.

Study Representativeness

A study representativeness table is included as Supplemental Table 10.

Discussion

In this phase 1 study of selinexor in pediatric patients with recurrent/refractory pediatric CNS and other solid tumors, the MTDs were determined to be 20 mg/m² BIW 3/1, and 35 mg/m² QW, with the latter deemed the MTD with the highest C_max for use in the dose expansion for HGG. DLTs were variable and included hematologic toxicity (mainly thrombocytopenia), increased transaminases, and neurologic symptoms, including fatigue/somnolence, cerebellar symptoms, and seizure. Selinexor PK were similar to those observed in a pediatric acute leukemia trial,¹⁴ but substantially different from those observed in an adult trial.⁹ Stable disease beyond 16 weeks (5–9 cycles) occurred in 13.5% of patients across all dose levels.

In adult trials, DLTs have been predominantly gastrointestinal, including nausea, vomiting, dehydration, and anorexia.⁹ Compared to the rates of GI toxicities seen in adults, the rates observed in children were similar overall (73% nausea, 45% anorexia, and 64% vomiting) but successfully managed with prophylactic antiemetics and appetite stimulants, including olanzapine, which has been shown to be particularly effective in ameliorating selinexor-related GI toxicity.¹⁶ In contrast, no hematologic DLTs were seen in an initial phase 1 trial in adults with solid tumors, and the overall rates of hematologic toxicity were substantially lower than in the current trial,⁹ although rates of hematologic toxicity in subsequent adult phase 1 solid tumor and lymphoma trials were more comparable to those seen in this pediatric trial.^17,18 Trials in children with relapsed or refractory leukemia arrived at higher MTD due, in part, to appropriate exclusion of hematologic DLTs, but prolongation of count recovery was also not observed.^14,15 The reason for higher frequency of hematologic toxicity in pediatric solid tumor subjects than in some adult trials is unclear. The current study population was heavily pretreated, with a median of 3 prior chemotherapy regimens and almost universal exposure to radiation therapy. Thrombocytopenia has been shown to be an on-target effect of selinexor via inhibition of thrombopoietin signaling during megakaryopoiesis.¹⁹ Currently, the thrombopoietin-receptor agonists (TRA) eltrombopag and romiplostim are FDA approved in both adults and children for the treatment of chronic immune thrombocytopenia, and the pediatric labeling extends to aplastic anemia for eltrombopag. No TRA has sought marketing approval for the management of chemotherapy-induced thrombocytopenia, but this class of agents seems likely to be effective as supportive care to manage selinexor dose intensity and exposure.²⁰

Neurologic DLTs, including acute cerebellar syndrome and severe fatigue, have been observed previously, both in adults²¹ and children. Two children on the phase 1 study of selinexor with fludarabine/cytarabine in relapsed leukemia experienced acute, reversible cerebellar toxicity at the highest dose (70 mg/m² BIW).¹⁴ The neurologic DLTs observed in our study were seen exclusively in patients with CNS tumors, who made up 69% of the study population. In adults with multiple myeloma, all patients receive concurrent dexamethasone, and the KING trial of selinexor in adults with recurrent glioblastoma recommended prednisone prophylaxis for all patients to mitigate nausea and fatigue.¹³ Our 2 patients with fatigue/somnolence DLTs on BIW selinexor recovered rapidly with dexamethasone treatment and were able to restart selinexor on a QW schedule without recurrence of symptoms. The use of prophylactic dexamethasone needs to be balanced with its potential to decrease selinexor’s blood-brain barrier penetration;²² in the case of neurologic toxicity, use of dexamethasone to treat these symptoms should be prioritized. In the dose-expansion of the weekly MTD in HGG subjects, no DLTs were observed and only 2/10 were taking concurrent dexamethasone.

Given the short half-life of selinexor,^9,10 we did not expect plasma, brain, or intratumoral accumulation of the drug even with BIW dosing. Our decision to evaluate QW dosing was based on several factors. Preclinical data demonstrated IC₅₀ levels for selinexor in a range of 5–200 nM for pediatric HGG lines.^1,23 Adults with recurrent GBM achieved intratumoral selinexor concentrations of 40–291 nM 2.6–4.6 hours after a 50 mg/m² dose, tolerated weekly dosing and had best responses at higher weekly dose levels.¹³ Furthermore, during our evaluation of BIW dosing, we demonstrated dose-proportional PK and higher plasma peak concentrations at 35 mg/m² than those achieved at the 20 mg/m² dose. At dose levels 35 and 45 mg/m², the average C_max was 599 and 755 ng/ml, respectively, exceeding the anticipated therapeutic threshold for HGG. The Lassman et al. study showed selinexor crosses the BBB and provided an initial PK/PD relationship between plasma and tumor concentrations.¹³ Our whole blood PD results demonstrate target engagement by selinexor across all dose levels, with a significant increase in XPO1 expression. This PD effect due to XPO1 degradation after selinexor binding with subsequent upregulation of mRNA expression has been observed in other studies;^9,14,24 however, as observed in our study, no relationship between plasma PK and the magnitude of XPO1 expression change in whole blood could be demonstrated. Although the relationship between selinexor PK and PD remains largely uncharacterized, preclinical data, along with all human PK data, provided valuable guidance for dose and schedule modifications for this study. Further studies are needed to determine the selinexor PK and PD relationship after repeated doses.

Differences in pediatric and adult PK included lower selinexor clearance in children, resulting in a 67% higher C_max and 40% higher systemic exposure (AUC_0–48h) after a 35 mg/m² dose (Supplemental Table 8). In children receiving selinexor 35 mg/m², the C_max of 599 ng/mL (1,351 nM) achieved at T_max of 3.4±3.9h was, in fact, greater than the C_2hr (967 nM) found in adults receiving 50 mg/m² (Supplemental Table 8). While the reasons for these differences are unclear, differences in PK between adults and children are generally attributed to differences in body size, body composition, and maturation of drug metabolizing enzymes. Given the ages of children enrolled in this study (6–20 years), activity of drug metabolizing enzymes should be at the adult levels, and differences are more likely due to body size and composition. Our study was limited to older children and adolescents due to the available selinexor tablet formulation, which is not suitable for use in younger children. Future studies using a more pediatric friendly liquid formulation will provide the opportunity to characterize selinexor PK in younger children and further explore the etiology of the observed pediatric-adult PK differences. Finally, selinexor absorption is increased when administered with food,¹⁷which may contribute to variability between individuals and between different studies. For patients with DLT, the exposure (AUC_0–24 and C_max) trended higher at each dose level but did not reach statistical significance (Supplemental Figure 1). Correspondingly, the BSA-adjusted clearance was decreased in patients with DLTs; however, this also did not reach statistical significance. Overall, the differences in PK profiles observed in our study underscore the need for pediatric-specific PK analysis, including the need to understand differences in brain penetration.

In conclusion, selinexor is tolerated in children with recurrent/refractory CNS and solid tumors. Toxicity was improved with QW dosing, with an MTD and initial RP2D of 35 mg/m² in heavily pretreated patients. Supportive care interventions, such as eltrombopag or romiplostim for thrombocytopenia and filgrastim for neutropenia, were not evaluated in this trial but could be considered in future studies. Given its histology-agnostic mechanism, CNS penetration, and these initial results showing prolonged SD in some patients with heavily pretreated malignancies, selinexor, alone or in combination, is worthy of future study in pediatric tumors with unmet need. Based on results from this trial, a phase 1/2 study of selinexor in combination with radiation for pediatric patients with newly diagnosed HGG (COG ACNS1821, NCT05099003) has been initiated with a plan to try to further escalate QW dosing in a treatment naïve population.

Statement of Translational Relevance:

In this study, we have determined the maximum tolerated dose and schedule of selinexor for heavily pretreated pediatric patients with recurrent/refractory solid tumors, including central nervous system tumors. We determined that the adverse effects of selinexor are mostly hematologic and neurologic, compared to mostly gastrointestinal in adults, although gastrointestinal adverse effects were still seen in this study. We found that selinexor’s pharmacokinetics were similar to those found in relapsed pediatric leukemia but substantially different than those seen in adult trials. We provide evidence and a methodology for measuring selinexor’s pharmacodynamic effects on XPO1 expression. Although no objective imaging responses were seen, a group of patients, including several with high-grade gliomas, had prolonged stable disease. Overall, our findings will inform the design of future selinexor clinical trials and the use of this FDA-approved targeted agent in pediatric patients with solid tumors.