ONC201 in Pediatric H3 K27M Gliomas

  • STATUS
    Recruiting
  • End date
    Jan 31, 2023
  • participants needed
    130
  • sponsor
    Chimerix
Updated on 16 May 2021
platelet count
renal function
cancer
corticosteroids
nitrosoureas
MRI
glomerular filtration rate
initial diagnosis
epilepsy
brain mri
progressive disease
neutrophil count
blood transfusion
bevacizumab
seizure
temozolomide
malignant glioma
recurrent glioma
dipg
diffuse intrinsic pontine glioma
dna sequencing
re-irradiation
mri of brain

Summary

This is a multicenter, open-label, seven arm, dose escalation, phase I study of oral ONC201 in pediatric patients with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and recurrent/refractory H3 K27M gliomas. Arm A will define the RP2D for single agent ONC201 in pediatric patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. This will allow for recurrent patients and also patients who have not yet recurred, but have completed radiation and will inevitably recur based on prior clinical experience and the literature. Arm B will define the RP2D for ONC201 in combination with radiation in pediatric patients with newly diagnosed DIPG. Arm C will determine intratumoral drug concentrations and biomarker expression in pediatric patients with midline gliomas. Arm D will determine H3 K27M DNA levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. Arm E will determine the RP2D for single agent ONC201 administered as a liquid formulation in Ora-Sweet to patients with DIPG and/or H3 K27M glioma. Arm F is a dose expansion cohort to confirm the safety and estimate the efficacy in recurrent H3 K27M-mutant glioma population at the RP2D. Arm G will define the RP2D for single agent ONC201 given on two consecutive days of each week in pediatric patients with glioma who are positive for the H3 K27M mutation and have completed at least one line of prior therapy.

Details
Condition Glioma, Diffuse Intrinsic Pontine Glioma, DIPG, Gliomas
Treatment ONC201
Clinical Study IdentifierNCT03416530
SponsorChimerix
Last Modified on16 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

2 to less than 19 years of age
Patient body weight must be above the minimum necessary for the patient to receive the ONC201 dose indicated for the currently enrolling dose level. The minimum body weight ranges from 10-27.5kg depending on the dose level
Arm A and G: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease. No more than two episodes of recurrence from radiotherapy and/or chemotherapy are allowed. Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or treatment effect will not be considered a recurrence. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available
Arm B: Patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG)
defined as tumors with a pontine epicenter and diffuse involvement of the
pons, are eligible with or without histologic confirmation. Post-mortem biopsy
is required if H3 K27M status of tumor is unknown and archival tumor tissue
not available
Arm C: Patients with midline gliomas are eligible with or without histologic
confirmation and must be eligible for tumor biopsy as deemed by the site
Investigator
Arm D: Patients with recurrent glioma who are positive for the H3 K27M
mutation (positive testing in CLIA laboratory), have completed at least one
line of prior therapy, must be willing to undergo serial lumbar puncture to
obtain cerebrospinal fluid (CSF), and must be scheduled to undergo sedated
MRIs. Local anesthesia for spinal tap is also allowed. Evidence of progression
is not required so that ONC201 may be administered to patients in the
maintenance setting or to patients with recurrent disease. No more than two
prior episodes of recurrence from radiotherapy and/or chemotherapy are
allowed. Use of bevacizumab solely for treatment of radiation necrosis
pseudoprogression, or treatment effect will not be considered a recurrence
Spinal tap should not be performed if treating clinician or lumbar puncture
proceduralist has concern of signs of elevated intracranial pressure
including recent worsening in headache or somnolence
Arm E: Patients with glioma who are positive for the H3 K27M mutation
(positive testing in CLIA laboratory) or have diagnosed diffuse intrinsic
pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse
involvement of the pons, are eligible with or without histologic confirmation
Patients must be 2-12 weeks from completion of first-line radiation. Evidence
of progression is not required so that ONC201 may be administered to patients
in the maintenance setting or to patients with recurrent disease
Arm F
Pediatric patients with histologically confirmed diagnosis of high-grade
glioma in any tumor sample with a known histone H3 K27M mutation identified by
IHC or DNA sequencing test performed in a CLIA setting. Evidence of
progressive disease on contrast-enhanced brain MRI as defined by RANO-HGG
criteria is required. Patients must have had previous therapy with at least
radiotherapy
\. Karnofsky 50 for patients 16 years of age, and Lansky 50 for patients < 16
years of age. For Arm F, Karnofsky 60 for patients 16 years of age, and Lansky
for patients < 16 years of age
\. From the projected start of scheduled study treatment, the following time
periods must have elapsed: 5 half-lives from any investigational agent, 4
weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from
nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever
is shorter) from other anti-tumor therapies. For patients who have received
radiotherapy, patients in any arm must be at least 2 weeks from the completion
of local palliative radiotherapy (re-irradiation for progressive disease or
upfront radiation at initial diagnosis). For Arm F, patients must be at least
days from prior radiation to the first dose of ONC201unless the progressive
lesion is outside of the high-dose radiation target volume or there is
unequivocal evidence of progressive tumor on a biopsy specimen
\. Adequate organ function defined as
Bone Marrow
Peripheral absolute neutrophil count (ANC) 1000/mm3 and
Platelet count 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
Renal Function
Creatinine clearance or radioisotope glomerular filtration rate (GFR)
mL/min/1.73 m2 or normal serum creatinine based on age as shown below or GFR
> 70ml/min/1.73m^2: Age < 5 years: 0.8 mg/dL maximum Age 5 to < 10 years: 1.0
mg/dL maximum Age 10 to < 15 years: 1.2 mg/dL maximum Age > 15 years: 1.5
mg/dL maximum
Liver Function
Total Bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of institutional normal and
SGPT (ALT) 110 U/L and
Serum albumin 2 g/dL
Neurologic Function
Patients with seizure disorder may be enrolled if seizure disorder is well
controlled
\. Ability to understand a written informed consent document, and the
willingness to sign it. Assent will be obtained when appropriate based on the
subjects age
\. All adverse events Grade > 1 related to prior therapies (chemotherapy
radiotherapy, and/or surgery) must be resolved to grade 1 or baseline, except
for alopecia and sensory neuropathy Grade 2, or other Grade 2 not constituting
a safety risk based on investigator's judgment, are acceptable
\. For patients post pubertal: Female patients must agree to use effective
contraception during the period of the trial and for at least 90 days after
completion of treatment. Male patients must be surgically sterile or must
agree to use effective contraception during the period of the trial and for at
least 90 days after completion of treatment. The decision of effective
contraception will be based on the judgment of the principal investigator
\. Corticosteroid dose must be stable or decreasing for at least 3 days
prior to the baseline CT or MRI scan
\. MRI brain and entire spine MRI within 14 days prior to start of study
drug for Arms A, B, C, E, F and G. Subjects undergoing screening for Arm D
must have an MRI of brain and entire spine within 3 months prior to start of
study drug. Subjects in Arm D will have a baseline MRI of brain and spine with
lumbar puncture after study consent is signed and other eligibility criteria
are fulfilled
\. For Arms A, B, C, D, F and G: Ability to swallow and retain orally
administered capsules
\. Archival tumor specimen: Subjects in all arms must submit at least 5
unstained slides from a tumor specimen that harbors H3 K27M mutation if
archival tissue is available. For subjects in Arms A, B, E or G, if no
archival tumor tissue is available, or if H3 K27M status of tumor is unknown
then subjects must agree to submit a post-mortem biopsy specimen. Subjects in
Arm C do not require prior tumor biopsy or confirmation of the presence of the
H3 K27M mutation. Subjects in Arm D must have confirmation of the presence of
the H3 K27M mutation in any glioma sample prior to enrollment. Subjects in Arm
F must submit at least 5 unstained slides from a tumor specimen that harbors
H3 K27M mutation. Note that the H3 K27M mutation is often reported as H3 K28M
in gene sequencing assays

Exclusion Criteria

For Arms A, B, D, E, F and G: Evidence of diffuse leptomeningeal disease or evidence of CSF dissemination
Current or planned participation in a study of another investigational agent or using an investigational device
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
Any known clinically significant active infection including bacterial, fungal or viral including hepatitis B (HBV), hepatitis C (HCV) or any underlying disease or in the recent past which could compromise enrollment and safety of the patient
Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared patient to receive ONC201. Receiving therapeutic agents known to prolong QT interval will be excluded, however the use of Zofran is permitted. History of CHF, or MI or stroke in the last 3 months will be excluded
Active illicit drug use or diagnosis of alcoholism
Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug
Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration
Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent dexamethasone is allowed
For Arm F: Exclusively non-contrast-enhancing disease or primary malignant lesion located in the pons or spinal cord
For Arm F: Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA)
Prior treatment with ONC201
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