Inclusion Criteria:

• Is able to understand the study procedures and agrees to participate in the study by providing written informed consent (by patient or legally authorized representative), and assent when applicable.

• Has histologically confirmed pheochromocytoma or paraganglioma that is unresectable as determined by the Investigator.

• Has failed, is not a candidate for, or has declined standard of care treatment for PCPG. There is no limit on the number of prior systemic therapies.

• Must have measurable disease per RECIST v1.1, as assessed by the Investigator.

  • Only measurable lesions per RECIST v1.1 may be selected as target lesions. Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth after completion of radiation.

• Has adequately controlled blood pressure defined as blood pressure ≤150/90 mmHg and with no change in antihypertensive medications (for patients with concomitant hypertension) for at least 14 days before the first dose of study treatment.

• Is ≥18 years of age.

• Is able to swallow oral tablets

• Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, assessed within 7 days before the first dose of study treatment.

• Has laboratory test results meeting the following parameters within 14 days before the start of study treatment:

  • Absolute neutrophil count ≥1.0 × 109/L and platelets ≥75 × 109/L.

  • Total bilirubin ≤1.5 × the upper limit of normal (ULN) (patients with Gilbert’s syndrome may be included with total bilirubin >1.5 × ULN if direct bilirubin is ≤1.5 × ULN).

  • Aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN.

    • Note: For patients with documented baseline liver metastasis, the following limits will apply: ≤5 × ULN for transaminase.

  • Creatinine clearance ≥50 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate >60 mL/min/1.73 m2) or serum creatinine ≤1.5 × ULN.

• Has an expected survival of at least 12 weeks, as predicted by the physician.

• Has pharmacologic control of catecholamine-associated symptoms if patient has functional disease.

Note: All patients with secretory PCPG should be evaluated in consultation by hypertension specialist with experience in the management of hypertension in the setting of catecholamine--secreting tumors (usually an endocrinologist, nephrologist, or a cardiologist), and in the setting of hormone-associated hypertension.

• Additionally, if available, the study center is to provide ≥15 unstained formalin-fixed paraffin-embedded slides from the patient’s tumor tissue.

Note: If a patient only has 1 measurable lesion per RECIST v1.1, the biopsy specimen should be obtained from a nontarget lesion or archival tissue. Bone biopsies should not be submitted

Exclusion Criteria:

• Has known hypersensitivity to ONC206 or any excipient used in the ONC206 study treatment formulation.

• Is unable or unwilling to abide by the study protocol or cooperate fully with the Investigator.

• Has active cardiac disease/condition including any of the following:

  • Corrected QT interval (QTc) >480 msec (based on the mean from triplicate electrocardiograms [ECGs] performed during Screening).

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

  • Unstable angina, acute myocardial infarction, or arterial bypass or percutaneous transluminal coronary angioplasty within 6 months before the first dose of study treatment.

• Has previous exposure to ONC206 or dordaviprone (ONC201) from any source.

• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Exceptions include patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, or Von Hippel-Lindau disease-associated tumors that do not require immediate surgery or intervention.

• Has received any of the following interventions within the specified time periods before the first dose of study treatment or plans to receive any of the following interventions during study participation:

  • Any prior anticancer therapy or investigational agents within 4 weeks or 5 half-lives, whichever is shorter. Note: Denosumab and zoledronic acid are permissible.

    • Any treatment with somatostatin analog or lanreotide within 21 days before the baseline Positron Emission Tomography (PET) scan.

  • Strong cytochrome P450 (CYP) inhibitors within 14 days.

  • Strong CYP inducers within 14 days.

  • Any radiotherapy within 14 days.

  • Any major surgery, open biopsy or significant traumatic injury within 1 month (30 days).

• Is pregnant, breastfeeding, or planning to become pregnant while receiving study treatment or within 3 months after the last dose. Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment.

Note: Female patients of childbearing potential or males with reproductive ability should follow contraceptive guidelines during the study and for at least 3 months (90 days) after the last dose of study treatment.

• Has uncontrolled intercurrent illness or any other medical, psychiatric, or social condition that, in the opinion of the Investigator, may interfere with patient safety or the ability to comply with study requirements.

• Has unresolved toxicities from previous locoregional, systemic, or any other therapies, defined as toxicities (other than Grade ≤2 neuropathy or alopecia) not yet resolved to the National Cancer Institute Common Terminology Criteria for Adverse Events Grade ≤1, or baseline and considered clinically significant; consult with Medical Monitor.

• Has an active infection that requires systemic therapy.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/18/2025. Questions regarding updates should be directed to the study team contact.