Clinical Trials /

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

NCT02323880

Description:

This phase I trial studies the side effects and best dose of selinexor in treating younger patients with solid tumors or high-grade gliomas that have come back (recurred) 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.

Related Conditions:
  • Glioma
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selinexor in Treating Younger Patients With Recurrent or Refractory Solid Tumors or High-Grade Gliomas
  • Official Title: A Phase 1 Study of Selinexor (KPT-330), a Selective XPO1 Inhibitor, in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors

Clinical Trial IDs

  • ORG STUDY ID: ADVL1414
  • SECONDARY ID: NCI-2014-02410
  • SECONDARY ID: ADVL1414
  • SECONDARY ID: ADVL1414
  • SECONDARY ID: ADVL1414
  • SECONDARY ID: UM1CA097452
  • NCT ID: NCT02323880

Conditions

  • Malignant Glioma
  • Recurrent Brain Neoplasm
  • Recurrent Childhood Central Nervous System Neoplasm
  • Recurrent Childhood Glioblastoma
  • Recurrent Lymphoma
  • Recurrent Malignant Solid Neoplasm
  • Refractory Central Nervous System Neoplasm
  • Refractory Lymphoma
  • Refractory Malignant Solid Neoplasm
  • WHO Grade III Glioma

Interventions

DrugSynonymsArms
SelinexorCRM1 Nuclear Export Inhibitor KPT-330, KPT-330, Selective Inhibitor of Nuclear Export KPT-330, SINE KPT-330Treatment (selinexor)

Purpose

This phase I trial studies the side effects and best dose of selinexor in treating younger patients with solid tumors or high-grade gliomas that have come back (recurred) 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.

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 central
      nervous system (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 orally (PO) twice weekly (days 1, 3, 8, 10, 15, and 17). Treatment
      repeats every 28 days for up to 24 courses in the absence of disease progression or
      unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (selinexor)ExperimentalPatients receive selinexor PO twice weekly (days 1, 3, 8, 10, 15, and 17). Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
  • Selinexor

Eligibility Criteria

        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 3-4 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 3-4 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 glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3
             x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 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; pregnancy tests
             must be obtained in girls who are post-menarchal; males or females of reproductive
             potential may not participate unless they have agreed to use an effective
             contraceptive 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; 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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of selinexor
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD will be the maximum dose at which fewer than one-third of patients experience dose limiting toxicity, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) version 4.0.

Secondary Outcome Measures

Measure:Antitumor effect of selinexor
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Will be measured.
Measure:Pharmacodynamics of selinexor
Time Frame:Pre-dose and 4 hours after dose on day 1 of course 1
Safety Issue:
Description:Will be measured.
Measure:Penetration, pharmacodynamic effects, and biologic effects of selinexor in tumor tissue of patients with recurrent/refractory HGG requiring resection
Time Frame:Up to time of surgical resection during course 1
Safety Issue:
Description:Will be measured.
Measure:Rate of objective radiographic response (medical patients)
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Response will be defined as either partial response or complete response on two consecutive 2-dimensional measurements on standard imaging done 4 weeks apart.
Measure:Progression free survival (surgical patients)
Time Frame:Six months from the start of treatment
Safety Issue:
Description:Will be measured.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

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