Clinical trial NCT03893487: Fimepinostat in Treating Brain Tumors in Children and Young Adults
Official title: A Target Validation Study of Fimepinostat in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG), Recurrent Medulloblastoma, or Recurrent High-Grade Glioma (HGG)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Diffuse Intrinsic Pontine Glioma
Recurrent Anaplastic Astrocytoma
Recurrent Glioblastoma
Recurrent Malignant Glioma
Recurrent Medulloblastoma
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Pediatric Neuro-Oncology Consortium
name: Cannonball Kids' Cancer Foundation
name: Curis, Inc.
First posted: 2019-03-28
Enrollment: 30
Sex: ALL
Minimum age (years): 3
Maximum age (years): 39
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This trial studies how well fimepinostat works in treating patients with newly diagnosed diffuse intrinsic pontine glioma, or medulloblastoma, or high-grade glioma that have come back. Fimepinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description: PRIMARY OBJECTIVES:

I. To confirm penetration of fimepinostat across the blood brain barrier (BBB) in children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG), recurrent medulloblastoma, or recurrent high-grade glioma (HGG) by measuring concentration of fimepinostat and metabolite in primary tumor tissue.

EXPLORATORY OBJECTIVES:

I. To assess pharmacokinetics (PK) of fimepinostat in plasma and tumor tissue of children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.

II. To assess pharmacodynamics (PD) of fimepinostat in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG as measured by phosphorylation and acetylation in tumor tissue.

III. To correlate acetylation and phosphorylation in tumor tissue with tissue and plasma PK levels.

IV. To assess the safety and tolerability of fimepinostat in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.

V. To assess preliminary efficacy of fimepinostat given as monotherapy after surgery in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG, as based on progression-free survival (PFS) and objective response rate (ORR) as appropriate.

OUTLINE:

Patients receive fimepinostat orally (PO) once daily (QD) on days -2 to 0. Within 2 hours of receiving fimepinostat on day 0, patients undergo tumor resection.

MAINTENANCE PHASE: Patients receive fimepinostat by mouth, once daily for days 1-5 each week. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity for up to 12 months from the time treatment begins. Should patients continue to derive clinical benefit, and not experience excess toxicity or progression, patients can continue to receive drug for up to 24 months or longer pending discussion with study chairs and study sponsor.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 5 years.

Eligibility criteria: Inclusion Criteria:

* Patients must have one of the following histologically confirmed diagnoses (histologic confirmation from initial diagnosis acceptable, as appropriate):

  * Stratum A: Newly diagnosed diffuse intrinsic pontine glioma (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. Patients with newly diagnosed DIPG will be eligible to enroll before or after standard of care radiation, but must be eligible for a biopsy. Newly diagnosed DIPG stratum should not have received prior therapy before the initiation of fimepinostat, with the exception of those patients who received temozolomide during radiation therapy or who previously received radiation as per standard of care and have not yet undergone a biopsy. All patients who have received therapy other than radiation and temozolomide should be discussed with study chair(s) prior to enrollment. Patients enrolling after standard of care radiation must be enrolled within 14 weeks of completion of radiotherapy.
  * Stratum B: Recurrent medulloblastoma (WHO grade IV), any molecular subtype
  * Stratum C: Recurrent high-grade glioma (HGG), including anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV)

    * 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. Recurrent DIPG will be eligible for stratum C; however, eligibility requires biopsy/resection is feasible in a region of tumor outside of the pons (i.e. cerebellar extension or new metastatic site). These patients should be discussed with study chair(s) prior to enrollment
* Patients must be able to swallow intact fimepinostat capsules or mini-tabs without chewing or crushing
* Patients must have body surface area (BSA) \>= 0.5 m\^2
* Patients must undergo tumor tissue collection as part of their standard of care

  * Minimum possible tissue collected must be equivalent to about 4-6 stereotactic core biopsies
* Prior Therapy: Patients in the medulloblastoma and HGG strata will be allowed to have undergone prior therapy including surgery, chemotherapy, and radiation therapy. Patients in the newly diagnosed DIPG stratum should not have received prior therapy before the initiation of fimepinostat, with the exception of those patients who received temozolomide during radiation therapy or who previously received radiation as per standard of care and have not yet undergone a biopsy. All patients who have received therapy other than radiation and temozolomide should be discussed with study chair(s) prior to enrollment. 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

  * Myelosuppressive chemotherapy: At least 21 days after last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
  * 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
  * 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
  * Monoclonal antibodies: At least 21 days after last dose of monoclonal antibody
  * Radiotherapy:

    * At least 2 weeks after local palliative radiotherapy (XRT)
    * At least 3 months from craniospinal XRT, or XRT to \> 50% pelvis
  * Surgery:

    * At least 21 days from major surgery (biopsy and central line placement/removal are not considered major)
* Corticosteroids: Subjects who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
* 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)
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 milliliters (mL)/minute (min)/1.73 m\^2 or
* A serum creatinine based on age/gender as follows:

  * Age: Maximum Serum Creatinine (mg/dL)
  * 3 to \< 6 years: 0.8 (male), 0.8 (female)
  * 6 to \< 10 years: 1 (male), 1 (female)
  * 10 to \< 13 years: 1.2 (male), 1.2 (female)
  * 13 to \< 16 years: 1.5 (male), 1.4 (female)
  * \>= 16 years: 1.7 (male), 1.4 (female)
* Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age
* Serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =\< 110 U/L
* Serum albumin \>= 2 g/dL
* Neurologic function:

  * Subjects with seizure disorder may be enrolled if well controlled
* Gastrointestinal function:

  * Diarrhea \< grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
* Metabolic function:

  * Non-fasting glucose \< 125 mg/dL without the use of antihyperglycemic agents

    * 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
* Cardiac function: corrected QT (QTc) \< 480 msec
* 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
* A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate

Exclusion Criteria:

* Subjects who have not recovered from acute adverse events due to therapeutic agents administered more than 4 weeks earlier
* Patients must not have received prior therapy with single-agent or combination histone deacetylase (HDAC) and Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors
* Subjects who are receiving any other investigational agent
* History of allergic reaction to compounds of similar chemical or biological composition to fimepinostat
* 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
* Patients with active human immunodeficiency virus (HIV) infection and with potential life-threatening consequences associated with immune-suppressive therapy
* Patients with history of type 1 or 2 diabetes mellitus
* Patients with gastrointestinal condition that could interfere with absorption or metabolism of fimepinostat

Primary outcomes:
measure: Penetration of fimepinostat across the blood brain barrier (BBB)
timeFrame: During surgery or biopsy
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles (CHLA)
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Minnesota Research Institute
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St Louis
state: Missouri
city: Columbus
country: United States
facility: Nationwide Children's
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Children's Primary
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Zürich
country: Switzerland
facility: The University Children's Hospital in Zurich
state: Zurich
Study officials:
affiliation: University of California, San Francisco
name: Sabine Mueller, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: