PNOC016: Fimepinostat in Treating Brain Tumors in Children and Young Adults

Sponsor

Sabine Mueller, MD, PhD (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03893487

Collaborator

Pacific Pediatric Neuro-Oncology Consortium (Other), Cannonball Kids' Cancer Foundation (Other), Curis, Inc. (Industry)

Enrollment

Locations

Arm

99.8

Anticipated Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Intrinsic Pontine Glioma Recurrent Anaplastic Astrocytoma Recurrent Glioblastoma Recurrent Malignant Glioma Recurrent Medulloblastoma	Drug: Fimepinostat Procedure: Therapeutic Conventional Surgery	Early Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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:

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.
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.
To correlate acetylation and phosphorylation in tumor tissue with tissue and plasma PK levels.
To assess the safety and tolerability of fimepinostat in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.
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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Aug 7, 2019

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (fimepinostat, tumor resection) Patients receive fimepinostat by mouth once daily, on Days -2 to 0. Within 2 hours of receiving fimepinostat on Day 0, patients undergo tumor resection or biopsy as part of their standard of care. 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.	Drug: Fimepinostat Fimepinostat capsules Other Names: CUDC-907 Procedure: Therapeutic Conventional Surgery Undergo surgery

Arm

Intervention/Treatment

Experimental: Treatment (fimepinostat, tumor resection)

Patients receive fimepinostat by mouth once daily, on Days -2 to 0. Within 2 hours of receiving fimepinostat on Day 0, patients undergo tumor resection or biopsy as part of their standard of care. 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.

Drug: Fimepinostat

Fimepinostat capsules

Other Names:

CUDC-907

Procedure: Therapeutic Conventional Surgery

Undergo surgery

Outcome Measures

Primary Outcome Measures

Penetration of fimepinostat across the blood brain barrier (BBB) [During surgery or biopsy]
Will be analyzed using descriptive statistics from results of fimepinostat concentrations measured within the tumor tissue collected at the time of a standard of care surgery or biopsy. Within each strata, Simon's two-stage design will be used.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 39 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles (CHLA)	Los Angeles	California	United States	90027
2	Rady Children's Hospital	San Diego	California	United States	92123
3	University of California, San Francisco	San Francisco	California	United States	94143
4	Children's National Medical Center	Washington	District of Columbia	United States	20010
5	University of Florida	Gainesville	Florida	United States	32611
6	Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
7	Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
8	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
9	University of Michigan Hospital	Ann Arbor	Michigan	United States	48109
10	Children's Minnesota Research Institute	Minneapolis	Minnesota	United States	55404
11	Washington University in St Louis	Saint Louis	Missouri	United States	63110
12	Nationwide Children's	Columbus	Ohio	United States	43205
13	Oregon Health and Science University	Portland	Oregon	United States	97239
14	Children's Hospital of Philadelphia (CHOP)	Philadelphia	Pennsylvania	United States	19146
15	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
16	Texas Children's Hospital	Houston	Texas	United States	77030
17	University of Utah, Children's Primary	Salt Lake City	Utah	United States	84113
18	Seattle Children's Hospital	Seattle	Washington	United States	98105
19	The University Children's Hospital in Zurich	Zürich	Zurich	Switzerland	8032