Clinical Trial Details
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NCT03295396 : ONC201 in Adults With Recurrent H3 K27M-mutant Glioma
PhasePhase 2
AgesMin: 18 Years Max: N/A
Inclusion Criteria:

1. Histologically confirmed diagnosis of high-grade glioma (any histology, including but
not limited to glioblastoma, astrocytoma, and oligodendroglioma) in any tumor sample
and presence of histone H3 K27M mutation by a CLIA-approved immunohistochemistry or
DNA sequencing test on any glioma tumor sample.

2. Unequivocal evidence of progressive disease on contrast-enhanced brain CT or MRI as
defined by RANO criteria, or have documented recurrent glioma on diagnostic biopsy.

3. Measurable disease by RANO criteria.

4. Patients must have had previous therapy with at least radiotherapy.

5. No more than two prior episodes of recurrence from radiotherapy and/or chemotherapy.
Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or
treatment effect will not be considered a recurrence.

6. Interval of at least 8 weeks from the completion of radiotherapy. If patients are
within 8 weeks of radiotherapy, they may still be eligible if they meet one or more of
the following criteria.

1. Progressive tumor is outside the original high-dose radiotherapy target volume as
determined by the treating investigator, or

2. Histologic confirmation of tumor through biopsy or resection, or

3. Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent
with true progressive disease, rather than pseudoprogression or radiation
necrosis obtained within 28 days of registration.

7. 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

8. 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.

9. Male or Female age =18 years.

10. Karnofsky Performance Status (KPS) = 60 (see Appendix A).

11. Adequate organ and marrow function as defined below, all screening labs should be
performed within 14 days of treatment initiation:

- leukocytes = 3,000/mcL

- absolute neutrophil count = 1,500/mcL

- platelets = 75,000/mcL

- hemoglobin > 8.0 mg/dL

- total bilirubin = 2.0 x upper limit of normal

- AST (SGOT)/ALT (SGPT) = 2.5 × upper limit of normal

- creatinine = ULN OR creatinine clearance =60 mL/min/1.73 m2 for patients with
creatinine levels above normal.

12. Contrast-enhanced head CT or brain MRI and entire spine MRI within 14 days prior to
start of study drug.

13. Corticosteroid dose must be stable or decreasing for at least 3 days prior to the
baseline CT or MRI scan.

14. The effects of ONC201 on the developing human fetus are unknown. For this reason,
women of childbearing potential (WOCBP) and men must agree to use adequate
contraception prior to study entry and for the duration of study participation and for
30 days after the last dose of therapy. Highly effective contraceptive measures
include: stable use of oral contraceptives such as combined estrogen and progestogen
and progestogen only hormonal contraception or other prescription pharmaceutical
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device
[IUD]; intrauterine hormone- releasing system (IUS); bilateral tubal ligation;
vasectomy and sexual abstinence.

1. WOCBP must have a negative serum or urine pregnancy test within 28 days of
initiation of dosing.

2. Contraception is not required for men with documented vasectomy.

3. Postmenopausal women must be amenorrheic for at least 12 months in order not to
be considered of childbearing potential.

4. Pregnancy testing and contraception are not required for women with documented
hysterectomy or tubal ligation.

15. Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1
cm2 of tumor surface area, or 20 unstained slides from the tumor tissue specimen if a
tumor block cannot be submitted. If a patient has had only a stereotactic biopsy, then
5 unstained slides may be accepted with prior approval from the Sponsor, however all
efforts must be made to obtain as close to 20 slides as possible.

16. Ability to be able to swallow and retain orally administered medication

17. Ability to understand and the willingness to sign a written informed consent document.
Only subjects who have capacity to consent will be enrolled in the study.

Exclusion Criteria:

1. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ONC201 or its excipients.

2. Current or planned participation in a study of an investigational agent or using an
investigational device.

3. Presence of diffuse leptomeningeal disease or evidence of CSF dissemination.

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.

5. Active infection requiring systemic therapy.

6. Pregnant and/or breastfeeding women or unable to maintain use of contraception while
on study and for 30 days after the last dose of study drug because ONC201 is novel
agent with unknown potential for teratogenic or abortifacient effects. Because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with ONC201, breastfeeding should be discontinued if the
mother is treated with ONC201.

7. Known HIV-positive test on combination antiretroviral therapy.

8. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias
or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared
patient to receive ONC 201. Receiving therapeutic agents known to prolong QT interval
will be excluded. History of CHF, or MI or stroke in the last 3 months will be

9. Active illicit drug use or diagnosis of alcoholism.

10. Tumors with known IDH1 (isocitrate dehydrogenase 1) or known IDH2 mutations as
determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing.
IDH1/2-mutant gliomas have a markedly longer overall survival rate compared to those
with IDH1/2-wildtype glioma (Parsons et al., 2008; Yan et al., 2009), indicating
IDH1/2-mutant gliomas have a distinct natural history.

11. Known additional malignancy that is progressing or requires active treatment within 3
years of start of study drug. Exceptions include basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or in situ melanoma or in situ cervical cancer
that has undergone potentially curative therapy.

12. Any surgery (not including minor diagnostic procedures such as lymph node biopsy)
within 2 weeks of baseline disease assessments; or not fully recovered from any side
effects of previous procedures. An interval of 1 week for stereotactic brain biopsy
from the start of study treatment is acceptable.

13. Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study
and within 72 hours prior to starting study drug administration.

14. 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.
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