Clinical Trials /

ONC201 in Adults With Recurrent H3 K27M-mutant Glioma



The primary objective of this phase II trial is to determine the efficacy and safety of ONC201, an oral small molecule imipridone DRD2 antagonist, in adult subjects with recurrent high-grade glioma. This study will test the research hypothesis that histone H3 K27M mutation sensitizes to oral administration of ONC201 in gliomas.

Related Conditions:
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Malignant Glioma
  • Oligodendroglioma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: ONC201 in Adults With Recurrent H3 K27M High-grade Glioma
  • Official Title: A Phase II, Open-label Study of ONC201 in Adults With Recurrent High-grade Glioma

Clinical Trial IDs

  • NCT ID: NCT03295396


  • Glioma




The primary objective of this phase II trial is to determine the efficacy and safety of ONC201, an oral small molecule imipridone DRD2 antagonist, in adult subjects with recurrent high-grade glioma. This study will test the research hypothesis that histone H3 K27M mutation sensitizes to oral administration of ONC201 in gliomas.

Trial Arms


Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed diagnosis of glioma (any histology, including but not limited
             to glioblastoma, astrocytoma, oligodendroglioma, malignant glioma, high-grade glioma,
             etc.) 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 can have had any number of prior therapies, however must have had previous
             therapy with at least radiotherapy.

          5. 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.

          6. 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

          7. 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.

          8. Male or Female age ≥18 years.

          9. Karnofsky Performance Status (KPS) ≥ 60.

         10. 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 OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with
                  creatinine levels above normal.

         11. Contrast-enhanced CT or MRI within 14 days prior to start of study drug.

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

         13. 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.

         14. 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.

         15. Ability to understand and the willingness to sign a written informed consent document.

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

          4. Active infection requiring systemic therapy.

          5. Pregnant and/or breastfeeding women 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

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

          7. 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

          8. Active illicit drug use or diagnosis of alcoholism.

          9. 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.

         10. 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.

         11. 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.

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

         13. Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing
             antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2
             weeks prior to starting treatment.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Best overall response rate by RANO


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oncoceutics, Inc.

Last Updated

October 30, 2017