Selinexor in Treating Younger Patients With Recurrent or Refractory Solid Tumors or High-Grade Gliomas

A Phase 1 Study of Selinexor (KPT-330), A Selective XPO1 Inhibitor, in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors

This phase I trial studies the side effects and best dose of selinexor in treating younger patients with solid tumors or central nervous system (CNS) tumors that have come back (recurrent) or do not respond to treatment (refractory). Drugs used in chemotherapy, such as selinexor, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Study Overview

• Status: Active, not recruiting
• Conditions: Malignant Glioma; WHO Grade 3 Glioma; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Recurrent Lymphoma; Recurrent Malignant Solid Neoplasm; Refractory Primary Central Nervous System Neoplasm; Recurrent Childhood Central Nervous System Neoplasm; Recurrent Brain Neoplasm; Recurrent Childhood Glioblastoma
• Intervention / Treatment: Other: Pharmacological Study; Drug: Selinexor

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) or the maximum tolerated dose (MTD) of the tablet formulation of selinexor in children with recurrent/refractory solid and CNS tumors.

II. To describe the toxicities of selinexor in children with recurrent/refractory solid and CNS tumors.

III. To characterize the pharmacokinetics of the tablet formulation of selinexor in children with recurrent/refractory solid and CNS tumors.

SECONDARY OBJECTIVES:

I. To determine the antitumor effect of selinexor in a preliminary manner in children with recurrent/refractory solid and CNS tumors.

II. To determine the pharmacodynamic properties of selinexor in children and adolescents with refractory solid tumors in plasma proteins and whole blood ribonucleic acid (RNA).

III. To explore the penetration, pharmacodynamic effects, and biologic effects of selinexor in tumor tissue of patients with recurrent/refractory high-grade gliomas (HGG) requiring resection.

IV. To further assess the toxicity and antitumor effects of selinexor in children with recurrent/refractory HGG in expanded cohorts following dose-escalation by measuring rate of objective radiographic response (medical patients) and rate of progression-free survival (PFS) six months from the start of treatment (surgical patients).

OUTLINE: This is a dose escalation study.

Patients receive selinexor PO on either a twice weekly (days 1, 3, 8, 10, 15, 17) or once weekly (days 1, 8, 15, and 22) schedule. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital For Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Saint Jude Children's Research Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have a body surface area (BSA) >= 0.84 m^2

• Diagnosis:

  • Part A: Patients with recurrent or refractory solid tumors, including lymphoma and CNS tumors, are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)
  • Part B: Patients with recurrent or refractory high grade glioma (World Health Organization [WHO] grade III/IV) including disseminated tumors (excluding diffuse intrinsic pontine glioma [DIPG]), not requiring surgical resection; patients must have had histologic verification of malignancy at original diagnosis or relapse
  • Part C: Patients with recurrent or refractory high grade glioma (WHO grade III/IV) and requiring surgical resection (excluding DIPG and disseminated tumors), who in the opinion of treating physicians, are medically stable to receive 2 doses of selinexor (8-10 days of treatment) before undergoing surgery without compromising the success of the procedure; note that if, in the opinion of treating physicians, current symptoms necessitate surgery before 2 doses will be able to be received, surgery should not be delayed to administer selinexor, and the patient would be ineligible for protocol therapy

• Disease status:

  • Part A: Patients must have either measurable or evaluable disease
  • Parts B and C: Patients must have measurable disease on imaging
• Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

  • Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
  • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
  • Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
  • Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • External beam radiation therapy (XRT): At least 14 days after local palliative XRT (small port); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation
  • Stem cell infusion without TBI: No evidence of active graft vs. host disease and at least 56 days must have elapsed after transplant or stem cell infusion
  • Patients must not have received prior exposure to selinexor
• For patients with solid tumors without known bone marrow involvement:
• * Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• * Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• * Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
• Patients with known bone marrow metastatic disease will be eligible for study if they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled on Part A must be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or

• A serum creatinine based on age/gender as follows:

  • =< 0.6 mg/dL (patients age 1 to < 2 years)
  • =< 0.8 mg/dL (patients age 2 to < 6 years)
  • =< 1 mg/dL (patients age 6 to < 10 years)
  • =< 1.2 mg/dL (patients age 10 to < 13 years)
  • =< 1.4 mg/dL (female patients age >= 13 years)
  • =< 1.5 mg/dL (male patients age 13 to < 16 years)
  • =< 1.7 mg/dL (male patients age >= 16 years)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN = 135 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
• Serum albumin >= 2 g/dL
• Serum amylase =< 1.5 x ULN
• Serum lipase =< 1.5 x ULN
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Patients must be able to swallow tablets whole
• Part C: Archived paraffin-embedded tissue (20 unstained slides or a tumor block) from a prior resection must be available as a control for correlative studies; if tissue blocks or slides are unavailable, the study chair must be notified prior to enrollment
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study, since there is yet no available information regarding human fetal or teratogenic toxicities; based on its mechanism of action and findings in animals, selinexor may cause fetal harm when administered to a pregnant woman; pregnancy tests must be obtained in girls who are post-menarchal; males with female partners of reproductive potential or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control- including a medically accepted barrier method of contraceptive method (e.g., male or female condom) for the entire period in which they are receiving protocol therapy and for at least 1 week following their last dose of study drug; abstinence is an acceptable method of birth control

• Concomitant medications

  • Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
  • Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible
• Patients with body mass index (BMI) < 3rd percentile for age, as defined by WHO criteria for patients 1-2 years of age and Centers for Disease Control and Prevention (CDC) criteria for patients > 2 years of age, are not eligible
• Patients with grade 3 ataxia or grade >1 extrapyramidal movement disorder are not eligible
• Patients with known macular degeneration, uncontrolled glaucoma, or cataracts are not eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (selinexor); Patients receive selinexor PO on either a twice weekly (days 1, 3, 8, 10, 15, 17) or once weekly (days 1, 8, 15, and 22) schedule. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.	Other: Pharmacological Study; Correlative studies; Drug: Selinexor; Given PO; Other Names: ATG-010; CRM1 Nuclear Export Inhibitor KPT-330; KPT-330; Selective Inhibitor of Nuclear Export KPT-330; SINE KPT-330; Xpovio; Nexpovio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Dose Limiting Toxicities of Selinexor	The number of toxicity evaluable patients experiencing a dose limiting toxicity at least possibly attributable to selinexor by study part, schema, and dose level.	Up to 28 days
Number of Adverse Events of Selinexor	The number of patients experiencing adverse events at least possibly attributable to selinexor by study part, schema, and dose level.	Up to 6 years 11 months
Area Under the Drug Concentration Curve of Selinexor	The median (min, max) of the area under the drug concentration curve evaluated at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post dose on day 1 for Selinexor by study part, schema, and dose level.	Up to 2 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antitumor Effect of Selinexor	Number of patients with best response using RECIST 1.1 criteria of partial response (at least a 30% decrease in the sum of the diameters of target lesions) or complete response (disappearance of all target and non-target lesions and any pathological lymph nodes must have reduction in short axis to <10 mm).	Up to 6 years 11 months
Pharmacodynamics of Selinexor	Median (min,max) ratio of XPO1 mRNA expression after treatment to pre-treatment by study part, schema, and dose	Up to 28 days
Pharmacodynamics of Selinexor in High-grade Glioma (HGG) Patients	Median (min,max) ratio of XPO1 mRNA expression after treatment to pre-treatment by study part, schema, and dose	Up to 28 days
Radiographic Response of Selinexor in High-grade Glioma (HGG) Patients	Number of HGG patients with radiographic response by study part, schema, and dose level.	Up to 6 years 11 months
Progression-free Survival of Selinexor in Surgical High-grade Glioma (HGG) Patients	Number of surgical HGG patients with 6-month progression-free survival using the Response Evaluation Criteria in solid tumors criteria (RECIST v1.1) defining best response of progressive disease including at least 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study and no prior stable disease, partial response, or complete response.	Up to 6 months

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Julia Glade-Bender, COG Phase I Consortium

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2015
• Primary Completion (Actual): September 30, 2022
• Study Completion (Estimated): September 22, 2024

Study Registration Dates

• First Submitted: December 16, 2014
• First Submitted That Met QC Criteria: December 23, 2014
• First Posted (Estimated): December 24, 2014

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplasms; Lymphoma; Glioblastoma; Recurrence; Glioma; Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms
• Other Study ID Numbers: ADVL1414 (Other Identifier: CTEP); UM1CA097452 (U.S. NIH Grant/Contract); NCI-2014-02410 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No