ADVL1414: A Phase 1 Study of Selinexor (KPT-330, IND#125052), a Selective XPO1 Inhibitor, in Recurrent and Refractory Pediatric Solid Tumors, Including CNS Tumors.

Why are we doing this research?

PURPOSE:

The investigators will conduct a phase 1 trial of Selinexor in children with recurrent or refractory solid tumors, including CNS tumors using the Rolling Six design. The aims of the trial will be to establish the maximum tolerated pediatric doses of tablet formulation; to investigate the toxicities, pharmacokinetics, and pharmacodynamics of Selinexor in children with cancer; and to preliminarily explore efficacy in pediatric solid and CNS tumors, including medical and surgical expansion cohorts of HGG patients.

DETAILED DESCRIPTION:

Primary Outcome Measures:

·         Recommended phase 2 dose (RP2D) or the maximum tolerated dose (MTD) [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]

·         Adverse events as assessed by (CTCAE) version 4.0 [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]

·         DLT will be defined as possibly, probably or definitely attributable to Selinexor. The DLT observation period for the purposes of dose-escalation will be the first cycle of therapy.

·         Pharmacokinetic Assessment of Selinexor Concentrations in Plasma Samples [ Time Frame: Days 1 and 2 of Cycle 1 ] [ Designated as safety issue: No ]

·         A descriptive analysis of pharmacokinetic (PK) parameters of Selinexor will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).Blood samples will be collected at the following time points: Pre-dose, and at 30 min, 1, 2, 3, 4, 6, 8, and 24 hours after the dose on Day 1. For Part C, An additional PK sample will be collected after 3-4 doses prior to Tumor Resection. Surgical resection should occur after dose on Day 8 but before dose on Day 15 of Cycle 1.

Type: Interventional

Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

AGES ELIGIBLE FOR STUDY: 12 Months to 21 Years

Who can participate?

ELIGIBILITY CRITERIA

Inclusion Criteria:

  • Age: Patients must be ≥ than 12 months and ≤ 21 years of age at the time of study enrollment.
  • BSA: Patients must have a BSA ≥ 0.84 m2.

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 CSF or serum tumor markers including alpha-fetoprotein or beta-HCG.
  • Part B: Patients with recurrent or refractory high grade glioma (WHO Grade III/IV) including disseminated tumors (excluding 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).

 

Disease Status: Patients must have either measurable or evaluable disease on Part A. Parts B & C: Patients must have measurable disease on imaging.

 

Therapeutic Options: 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.

 

Performance Level: 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.

 

Prior Therapy

  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy.
  • 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.
  • Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody. (See table on DVL homepage listing monoclonal antibody half-lives.)
  • XRT: At least 14 days after local palliative XRT (small port); At least 150 days must have elapsed if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At least 42 days must have elapsed if other substantial 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.

Organ Function Requirements

Adequate Bone Marrow Function Defined as:

  • For patients with solid tumors without known bone marrow involvement:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3
  • Platelet count ≥ 100,000/mm3 (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 RBC transfusions)
  • Patients with known bone marrow metastatic disease will be eligible for study if they have an ANC ≥ 750/mm3 and platelet count ≥ 50,000/mm3 (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.
  • Adequate Renal Function Defined as:
  • Creatinine clearance or radioisotope GFR ≤ 70 ml/min/1.73 m2 or

Adequate Liver Function Defined as:

  • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
  • SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
  • SGOT (AST) ≤ 125 U/L. For the purpose of this study, the ULN for SGOT is 50 U/L.
  • Serum albumin ≥ 2 g/dL.
  • Adequate Pancreatic Function Defined as:
  • 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.
  • Informed Consent: 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:

  • Pregnancy or Breast-Feeding 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. 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 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.
  • 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.
  • Infection: 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 BMI < 3rd percentile for age, as defined by WHO criteria for patients 1-2 years of age and 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.
  • Patients must not have received megestrol acetate or cyproheptadine for 7 days prior to study enrollment for Dose Levels 1-3.

Ages

  • From 1 to 21 years old

Conditions

  • Lymphoma Hodgkin Relapse
  • Lymphoma Non Hodgkin Relapse
  • Brain Spinal Tumors Medulloblastoma Relapse
  • Brain Spinal Tumor Low Grade Glioma Relapse
  • Brain Spinal Tumor DIPG Relapse
  • Brain and Spinal Tumor Ependymoma Relapse
  • Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Brain Spinal Neurofibromatosis OPG
  • Brain Spinal Other Germ Cell Tumor
  • Brain Spinal Other Choroid Plexus Tumor
  • Brain Spinal Other Craniopharyngioma
  • Brain Spinal Other ATRT
  • Brain Spinal Other All Other
  • Sarcoma Osteosarcoma Relapse
  • Sarcoma Ewing Relapse
  • Sarcoma Rhabdomyosarcoma Relapse
  • Neuroblastoma Relapse - Refractory
  • Liver Relapse - Refractory
  • Kidney Relapse - Refractory
  • Solid Tumor Retinoblastoma Relapse - Refractory
  • Solid Tumor Neurofibromatosis Sarcoma MPNST Relapse - Refractory
  • Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Solid Tumor Melanoma Relapse - Refractory
  • Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Solid Tumors - All Other
  • Adult - Kidney Relapse - Refractory
  • Adult - Liver Relapse - Refractory
  • Adult - Lymphoma Hodgkin Relapse
  • Adult - Lymphoma Non Hodgkin Relapse
  • Adult - Brain Spinal Tumors Medulloblastoma Relapse
  • Adult - Brain Spinal Tumor Low Grade Glioma Relapse
  • Adult - Brain Spinal Tumor DIPG Relapse
  • Adult - Brain and Spinal Tumor Ependymoma Relapse
  • Adult - Sarcoma Osteosarcoma Relapse
  • Adult - Sarcoma Ewing Relapse
  • Adult - Sarcoma Rhabdomyosarcoma Relapse
  • Adult - Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Adult - Brain Spinal Neurofibromatosis OPG
  • Adult - Brain Spinal Other ATRT
  • Adult - Brain Spinal Other Choroid Plexus Tumor
  • Adult - Brain Spinal Other Craniopharyngioma
  • Adult - Brain Spinal Other Germ Cell Tumor
  • Adult - Brain Spinal Other All Other
  • Adult - Neuroblastoma Relapse - Refractory
  • Adult - Solid Tumor Retinoblastoma Relapse - Refractory
  • Adult - Solid Tumor Neurofibromatosis Sarcoma MPNST Relapse - Refractory
  • Adult - Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Adult - Solid Tumor Melanoma Relapse - Refractory
  • Adult - Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Adult - Solid Tumors - All Other

Contact

For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology / Oncology
3333 Burnet Ave., Cincinnati OH 45229-3039

Phone: 513-636-2799

Email: cancer@cchmc.org