human stem cell derived neurons

Fimepinostat in Treating Brain Tumors in Children and Young Adults (PNOC016)

 

Summary

This phase I clinical trial will evaluate fimepinostat as a treatment for patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), recurrent medulloblastoma, or recurrent high-grade glioma (HGG). 

Fimepinostat is an orally administered small molecule drug that inhibits HDAC and PI3K enzymes, two classes of proteins implicated across multiple cancers: 

  • HDAC enzymes are involved in regulating gene expression. However in cancer cells, HDACs have been found to function incorrectly through dysregulation of oncogenes and tumor suppressor genes. 
  • In normal cells, the molecules in the PI3K pathway deliver signals to one another that regulate important processes such as cell proliferation, natural cell death (also called apoptosis) and blood vessel development. However, many pediatric gliomas have abnormal activation of the PI3K pathway, which is frequently associated with tumor cell growth and survival. 

By blocking both HDAC and PI3K enzymes, fimepinostat may inhibit tumor growth and survival through multiple pathways. 

In this study, fimepinostat will be given prior to the patients undergoing tumor resection or biopsy. One of the study’s objectives is to determine how well fimepinostat crosses the blood brain barrier, so tumor samples will be analyzed for fimepinostat concentration. 

This phase I study will evaluate fimepinostat as a treatment for children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, and recurrent HGG. All eligible participants will receive the following treatment:

  • Experimental Group: fimepinostat + tumor resection/biopsy

 

Inclusion Criteria
  1. Patients must have one of the following histologically confirmed diagnoses (histologic confirmation from initial diagnosis acceptable, as appropriate):
    1. Stratum A: Newly diagnosed diffuse intrinsic pontine glioma (DIPG) (World Health Organization [WHO] grade II-IV)- this stratum does not require tissue confirmation at time of enrollment, but diagnostic confirmation will be required to continue on study after biopsy
    2. Stratum B: Recurrent medulloblastoma (WHO grade IV), any molecular subtype
    3. Stratum C: Recurrent high-grade glioma (HGG), including anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV)
    4. Stratum B & C: Patients in the recurrent medulloblastoma or recurrent HGG arm can have locally recurrent or disseminated disease, provided resection/biopsy would still be clinically indicated. Disseminated disease can be diagnosed by imaging or cerebrospinal fluid (CSF) cytology
  2. Patients must be able to swallow intact fimepinostat capsules or mini-tabs without chewing or crushing
  3. Patients must have body surface area (BSA) >= 0.5 m^2
  4. Patients must undergo tumor tissue collection as part of their standard of care
    1. Minimum possible tissue collected must be equivalent to about 4-6 stereotactic core biopsies
  5. Strata B & C: Patients in the medulloblastoma and HGG strata will be allowed to have undergone prior therapy including surgery, chemotherapy, and radiation therapy. Patients in the DIPG stratum are not allowed to have prior therapy before the initiation of fimepinostat. Patients must have fully recovered from acute side effects related to previous anti-cancer therapies. Patients undergoing radiation during protocol therapy will not be permitted to receive other concomitant agents with radiation and pending initiation of maintenance with fimepinostat
    1. Myelosuppressive chemotherapy: At least 21 days after last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
    2. Hematopoietic growth factors: At least 14 days after last dose of a long-acting growth factor or 7 days after short-acting growth factor or beyond time during which adverse events are known to occur
    3. Biologic (anti-neoplastic agent): At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur
    4. Monoclonal antibodies: At least 21 days after last dose of monoclonal antibody
    5. Radiotherapy:
      1. At least 2 weeks after local palliative radiotherapy (XRT)
      2. At least 3 months from craniospinal XRT, or XRT to > 50% pelvis
    6. Surgery:
      1. At least 21 days from major surgery (biopsy and central line placement/removal are not considered major)
  6. Corticosteroids: Subjects who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
  7. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  8. Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  9. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 milliliters (mL)/minute (min)/1.73 m^2 or
  10. A serum creatinine based on age/gender as follows:
    1. Age: Maximum Serum Creatinine (mg/dL)
    2. 3 to < 6 years: 0.8 (male), 0.8 (female)
    3. 6 to < 10 years: 1 (male), 1 (female)
    4. 10 to < 13 years: 1.2 (male), 1.2 (female)
    5. 13 to < 16 years: 1.5 (male), 1.4 (female)
    6. >= 16 years: 1.7 (male), 1.4 (female)
  11. Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  12. Serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 110 U/L
  13. Serum albumin >= 2 g/dL
  14. Neurologic function:
    1. Subjects with seizure disorder may be enrolled if well controlled
  15. Gastrointestinal function:
    1. Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
  16. Metabolic function:
    1. Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents
    2. If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents, patient will meet adequate metabolic function criteria
  17. Cardiac function: corrected QT (QTc) < 480 msec
  18. The effects of fimepinostat on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 30 days after completion of fimepinostat administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  19. A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Subjects who have not recovered from acute adverse events due to therapeutic agents administered more than 4 weeks earlier
  2. Patients must not have received prior therapy with single-agent or combination histone deacetylase (HDAC) and Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors
  3. Subjects who are receiving any other investigational agent
  4. History of allergic reaction to compounds of similar chemical or biological composition to fimepinostat
  5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
  6. Patients with active human immunodeficiency virus (HIV) infection and with potential life-threatening consequences associated with immune-suppressive therapy
  7. Patients with history of type 1 or 2 diabetes mellitus
  8. Patients with gastrointestinal condition that could interfere with absorption or metabolism of fimepinostat
     

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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