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Protocol Details

A First-In-Human Phase I Single-Agent Dose-Escalation, Food Effect and Dose Expansion Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required


Population Exclusion(s)

Pregnant Women;


Brain Tumors;
Neuro-Oncology Tumors;

Recruitment Keyword(s)



Anaplastic Glial Neoplasms;
Primary CNS Sarcomas;
Diffuse Midline Gliomas and Histone Mutated Gliomas

Investigational Drug(s)


Investigational Device(s)



Drug: ONC206
Other: Food effect

Supporting Site

National Cancer Institute


A new drug called ONC206 may stop cancer cells from growing. It induces a stress response to kill brain tumor cells but not normal cells. Researchers want to see if it can help people with central nervous system (CNS) cancers.


To test how safe and how well ONC206 works in treating recurrent and rare primary CNS neoplasms.


People age 18 years and older with a recurrent and rare primary CNS cancer


Participants will be screened with:

Medical history

Neurological exam

Physical exam

Evaluations of their ability to perform typical activities and how their nervous system is functioning

Questionnaire about cancer-related symptoms

Electrocardiogram to assess heart health

Blood and urine tests

Pregnancy test (if needed)

Tumor biopsy (if needed)

Tumor assessment with magnetic resonance imaging (MRI) or computed tomography scan. For MRI, a contrast dye may be given through an intravenous catheter.

Participants must co-enroll on NCI Natural History Study 16-C-0151.

Participants will take ONC206 as a capsule by mouth. They may take it weekly for up to 1 year.

Some participants will fast or eat high-fat foods to see if this affects how ONC206 is absorbed in the body.

Participants will visit the NIH Clinical Center every 4 weeks. They will repeat some of the screening tests.

About 30 days and 90 days after their last dose of ONC206, participants will have follow-up visits at NIH. They may provide tumor imaging records for up to 6 months after they complete the study.

Active participation will last about 2 years. Long-term follow-up will include a monthly phone call for the rest of the participant s life.

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Patients must meet all the following criteria to participate in the study:

1. Patients aged >=18 years with a recurrent, primary CNS neoplasm. For all cohorts, patients must have a histologically confirmed primary CNS neoplasm. Primary CNS neoplasms in this study include, but are not limited to, the following: glioblastoma and glioblastoma histologic subtypes, gliosarcoma, primary CNS sarcomas, anaplastic glial neoplasms including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed neuronal-glial tumors, and pilocytic astrocytoma with anaplastic features, diffuse astrocytoma, oligodendroglioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, diffuse midline gliomas and histone mutated gliomas, ependymoma, anaplastic ependymoma, and all ependymoma subtypes, medulloblastoma and all medulloblastoma subtypes, atypical teratoid/rhabdoid tumor, primary CNS embryonal/primitive neuroectodermal tumors, atypical and anaplastic meningiomas, choroid plexus tumors, and pineal region tumors.

2. Patients must have recurrent and measurable disease as defined by RANO criteria, using either the HGG and/or low-grade glioma (LGG) RANO criteria based on tumor type, after having received established standard of care treatment for their disease and have no standard treatment options available as determined by the investigators. There is no limit on the number of total recurrences or prior therapies. However, prior therapies with known clinical benefit (including radiation) for specific tumor types are required. If patients are deemed ineligible for such therapies in the opinion of the Investigator, the Investigator must document the reason the patient is considered ineligible.

3. Patients must have a Karnofsky Performance Score (KPS) of greater than or equal to 70. Patients with severe paraparesis/paraplegia who need minimal assistance for self-care due to their motor deficit but are otherwise functionally independent will be considered eligible.

4. Patients must not have received prior investigational or approved cytotoxic chemotherapy within 28 days prior to the first dose of study drug (Cycle 1, Day 1); 42 days in the case of nitrosoureas; 42 days in the case of bevacizumab; 28 days or 5 half-lives (whichever is less; but not less than 14 days) in case of investigational or approved molecularly targeted agent; 14 days in the case of radiotherapy.

5. Patients will be required to enroll on the NCI NOB natural history study (Study 16-C-0151).

6. Patients with AEs Grade >=2 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have all their AEs resolved prior to the first dose of study drug (Cycle 1, Day 1), except for alopecia or neuropathy; Grade 1-2 lymphopenia is allowed.

7. Patients must not have undergone major surgery 4 weeks prior to the first dose of study drug (Cycle 1, Day 1) and must have completely recovered from any surgery (minor surgical procedures such as skin biopsies and port placement done on an outpatient basis do not require a waiting period).

8. Patients must have normal organ and marrow function as defined below:

-a. Absolute neutrophil count (ANC) >=1,500/mcL.

-b. Platelets >=100,000/mcL.

-c. Hemoglobin >=9.0 mg/dL without transfusion in 2 prior weeks.

-d. Total bilirubin within normal range. For patients with liver metastases, serum bilirubin <=1.5 (SqrRoot) upper limit of normal (ULN).

-e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <=2.5 (SqrRoot) ULN.

-f. Measured or estimated creatinine clearance (CLcr) >=40 mL/minute for patients with creatinine levels above normal. CLcr will be calculated by the Cockcroft-Gault equation for renal function.

9. Patients must provide a tumor specimen (paraffin-embedded block and/or frozen tissue) from a prior resection or biopsy available that is sufficient to perform biomarker assays, >=15 unstained slides for IHC analysis must be received by the NOB by the first dose of study drug (Cycle 1, Day 1). For patients with >=10 to <15 slides, eligibility will be reviewed on a case-by-case basis.

10. Dependent upon dose level assignment and drug formulation (i.e., capsules vs. PIB), patients must be able to either swallow oral capsules or swallow liquids.

11. Patients must provide study-specific informed consent prior to enrollment. No Durable Power of Attorney or Next of Kin can provide initial consent.

12. Patients must be able to tolerate a magnetic resonance imaging (MRI) study with intravenous gadolinium contrast.

13. Patients must be fully vaccinated for coronavirus disease 2019 (COVID-19) and if applicable, up to date, as defined by the Center for Disease Control guidance for patients who are moderately or severely immunocompromised

-a. Given the experimental nature of this treatment, patients on this trial will be considered moderately or severely immunocompromised for the purpose of COVID-19 vaccination requirements.

-b. Patients must have received required vaccination(s) and boosters (if applicable) by the time of signing consent and be considered fully immunized (typically 2 weeks after final vaccination) by the first dose of study drug (Cycle 1, Day 1). Vaccination is mandated because ONC206 is an anti-cancer therapy and may result in immunosuppression, which could increase the likelihood of morbidity or mortality associated with COVID-19 infection, and vaccination is now considered standard of care for oncology patients undergoing cancer treatment.

14. Patients must have a negative COVID-19 test within 72 hours of the first dose of study drug (Cycle 1, Day 1). Patients who had documented COVID-19 infection within 90 days of treatment but more than 20 days from infection do not need to be tested and are eligible if they fulfill the eligibility requirement regarding adequate vaccination (see Inclusion Criterion #15).

15. Patients must agree to follow study site requirements to limit transmission of COVID-19, such as wearing masks, social distancing, and maintaining good hand hygiene even after vaccination.


Patients who meet any of the following criteria will be excluded from the study:

1. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206 (e.g., ONC201) or its excipients.

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

3. Patients who are unable or unwilling to abide by the study protocol or cooperate fully with the investigator.

4. Patients with a known HIV-positive test on combination anti-retroviral therapy are ineligible for this initial first-in-human trial because of the potential for PK interactions with ONC206.

5. Patients with active cardiac disease, including any of the following:

-a. Corrected QT interval (QTc) >=470 msec on screening electrocardiogram (ECG; using the QTc by Fridericia s [QTcF] formula)

-b. Angina pectoris that requires the use of anti-anginal medication

-c. Ventricular arrhythmias except for benign premature ventricular contractions

-d. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication

-e. Conduction abnormality requiring a pacemaker

-f. Valvular disease with documented compromise in cardiac function

-g. Symptomatic pericarditis

6. Patients with a history of cardiac dysfunction including any of the following:

-a. Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction function

-b. History of documented congestive heart failure (New York Heart Association functional classification III-IV)

-c. Documented cardiomyopathy

7. Patients who have had an ischemic or hemorrhagic stroke in the last 3 months. If the patient has had a recent tumor resection, cerebral ischemic or hemorrhagic changes that occur peri-operatively are not an exclusion.

8. Patients with refractory epilepsy are excluded. Patients with primarily or secondarily generalized seizures in the 28 days prior to study enrollment will be excluded. Peri-operative seizures, defined as seizures occurring within the 7 days after a stereotactic biopsy, open biopsy, or surgical resection will not be an exclusion as long as the patient has had no generalized seizures starting 8 days after the surgical procedure. Patients with prior seizures must be on stable doses of 1 or 2 seizure medications for at least 14 days prior to study enrollment.

9. Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ONC206 (uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

10. Patients who have been treated with any hematopoietic colony-stimulating growth factors (CSFs) (e.g., granulocyte-CSF, granulocyte-macrophage-CSF) <=2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued.

11. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant.

12. Patients who are taking strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, 2D6,

1A2, 2C9, and 2C19 are excluded at least 14 days prior to the first dose of study drug (Cycle 1, Day 1) and throughout the study.

13. Women who are pregnant or breast feeding.

14. Women of child-bearing potential with a positive serum pregnancy test <=72 hours prior to the first dose of study drug (Cycle 1, Day 1).

15. Patients who are receiving concomitant standard and/or investigational anti-cancer therapy.

16. Patients with alcohol or substance abuse which, in the opinion of the Investigator, would interfere with compliance or safety.

17. Patients with the presence of any other serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with patients safety, obtaining informed consent or compliance to the study procedures as determined by the Investigators. (Patients with contraindications to COVID-19 vaccination will not be eligible for this study.)

18. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, or men who do not agree to use highly effective contraception during treatment and for 16 additional weeks after the final dose of study drug.

Highly effective contraception is defined as either:

-True abstinence: When this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

-Sterilization: Females must have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

-Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.

-If patients are not practicing true abstinence and/or if the patient or sexual partner have not had a sterilization procedure as listed above, patients and their sexual partners must follow double barrier contraception in accordance with the guidelines for contraception below:

--Females of childbearing potential:

---Must use an intrauterine device or intrauterine system, during dosing of any study agent and for 16 weeks after final dose of study drug; or

---Must use a double barrier method of contraception: use of an occlusive cap (diaphragm or cervical/vault cap) with spermicide for women combined with use of a condom by their male partners capable of conceiving offspring.

---Males capable of conceiving offspring must use condoms during dosing of study agent and for an additional 16 weeks after final dose of study drug.

Note: Oral, implantable, or injectable contraceptives may be affected by CYP interactions, and are therefore not considered effective for this study.

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Not Provided

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Principal Investigator

Referral Contact

For more information:

Mark R. Gilbert, M.D.
National Cancer Institute (NCI)
(240) 760-6023

NCI NOB Referral Group
National Cancer Institute (NCI)

(866) 251-9686

NCI NOB Referral Group

(240) 760-6010

Clinical Trials Number:


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