Phase 2 Study of ONC201 in Neuroendocrine Tumors

The purpose of this study is to learn if a new drug, ONC201 can make tumors become smaller or go away completely. Investigators also want to learn if ONC201 can prevent new deposits of cancer from appearing in new places in participants (metastases). A phase 2 study of ONC201 in PC-PG (pheochromocytoma-paraganglioma) and other neuroendocrine tumors will determine whether inhibition of DRD2 (a member of the dopamine receptor family) is safe in unresectable, recurrent, locally advanced, refractory, or metastatic neuroendocrine cancers including PC-PG, desmoplastic small round cell tumor (DSRCT), Ewing sarcoma (PNET) or any other neuroendicrine tumor with a catecholamine or dopamine biomarker or autocrine or paracrine dependence on dopamine including cholangiocarcinoma and adrenal cortical carcinoma. ONC201 is an investigational (experimental) agent and has a favorable safety profile in phase 1 and early phase 2 clinical trials in advanced cancers. This study design has been chosen to see whether ONC201 is associated with reduction of anti-hypertension medications, safety and significant efficacy against neuroendocrine tumors, especially PC-PG.

Primary Objective To demonstrate objective responses using MRI or CT, and/or PET-CT imaging. The same CT or MRI imaging to assess disease burden at study entry will be compared at week 6 and 3 months. Patients without progression at 3 months will continue treatment and have imaging at 6, 9 and 12 months after study entry. Metabolic response and/or biomarkers will be compared with study entry PET-CT and scans at 6 weeks, 3 months and 12 months. Secondary Objectives Progression - free Survival: This will be calculated according to Response Evaluation Criteria In Solid Tumors (RECIST) or development of new disease Overall survival: Overall survival will be determined by email or telephone contact. Study Design: Phase 2 open-label fixed dose study Metastatic neuroendocrine tumors including PC-PG are rare diseases. The current recommended phase II dose of 625 mg orally on 2 consecutive days every week will be used. The same imaging at study entry will be used at subsequent time points (CT or MRI for week 6 and 3, 6, 9, and 12 months) Imaging modality choice will be influenced by the quality of prior scans of the subject and will be ordered so clinical comparison is possible. Because of travel and lodging considerations associated with the COVID-19 pandemic, some information by the study team/PI may be obtained using virtual visits and 2nd read of scans sent to Cleveland Clinic

Complete Response (CR) Disappearance or fibrosis of all target lesions. Any pathologic lymph nodes must have reduction in short axis to <10mm and standardized uptake value (SUV) is <4. Partial Response (PR) At least 30% decrease in sum of longest diameters of target lesions (compared to initial on study baseline) and any decrease in SUV in Fludeoxyglucose 18F (18FDG) imaging Stable disease (SD) 0-29% decrease in sum of longest diameters of target lesions (compared to initial on study baseline) or 0-19% increase in sum of longest diameters of target lesions (compared to initial on study baseline). SUV may increase or decrease Progressive disease 20% or more increase of sum of longest diameters of target lesions (compared to initial on study baseline). The sum must also be at an increase of at least 5mm or one or more new lesions that are considered metastatic disease

Average time from beginning of treatment to progression, death, or one year, whichever comes first. An underlying clinical benefit rate of 25% would indicate that ONC201 has a therapeutic effect, whereas an underlying rate <5% would indicate a lack of activity

to achieve this secondary endpoint of anti-hypertensive medication reduction in PC-PG subjects (N=12) data at 3 months will be required. An underlying clinical benefit rate of 25% would indicate that ONC201 has a therapeutic effect, whereas an underlying rate <5% would indicate a lack of activity

"Subjects must have a unresectable, recurrent, locally advanced, refractory, or metastatic neuroendocrine tumor including pheochromocytoma-paraganglioma (PC-PG), DSRCT, Ewing Sarcoma or PNET, or any neuroendocrine tumor with a catecholamine or dopamine biomarker or autocrine or paracrine dependence on dopamine including cholangiocarcinoma and adrenal cortical carcinoma (ACC). There is no limit on number of prior therapies. Age ≥14 years. Subjects must have normal organ and marrow function as defined below. Studies should be done within 3 weeks prior to enrollment Hemoglobin ≥ 10.0 g/dl Leukocytes ≥ 1500/mcL Absolute neutrophil count ≥ 1,000/mcL Platelet count ≥ 75000/mcL Total bilirubin within 1.5 x normal institutional limits AST (SGOT) ≤ 5 X institutional upper limit of normal ALT (SGPT) ≤ 5 X institutional upper limit of normal Serum Creatinine <3.0mg/dL 5 1 lesion detectable on CT, MRI, 18FDG PET-CT 6 Subjects must have the ability to understand and the willingness to sign a written informed consent document. 7: Karnofsky or if <16 years old Lansky Play Performance status ≥ 60%

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Anderson PM, Trucco MM, Tarapore RS, Zahler S, Thomas S, Gortz J, Mian O, Stoignew M, Prabhu V, Morrow S, Allen JE. Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor. Clin Cancer Res. 2022 May 2;28(9):1773-1782. doi: 10.1158/1078-0432.CCR-21-4030.