Phase 2 Study of ONC201 in Neuroendocrine Tumors

• ClinicalTrials.gov Identifier: NCT03034200
• Recruitment Status: Completed
• First Posted: January 27, 2017
• Last Update Posted: December 5, 2022
• Sponsor: Peter Anderson
• Information provided by (Responsible Party): Peter Anderson, Case Comprehensive Cancer Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Neuroendocrine Tumor; Metastatic Neuroendocrine Tumor	Drug: ONC201	Phase 2

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of ONC201 in Neuroendocrine Tumors
• Actual Study Start Date: August 2, 2017
• Actual Primary Completion Date: November 30, 2022
• Actual Study Completion Date: November 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: ONC201 phase 2 d1d2 weekly cohort; 625 mg ONC201 by mouth daily for 2 consecutive days weekly	Drug: ONC201; 625mg ONC201 will be given on two consecutive days each week

Outcome Measures

Primary Outcome Measures :

1. Tumor response according to RECIST Criteria [ Time Frame: Up to 1 Year ]

   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

Secondary Outcome Measures :

1. Average duration of lack of progression: Clinical response [ Time Frame: Up to 1 Year ]
   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
2. Overall survival [ Time Frame: Up to 1 Year ]
   time from beginning of treatment until death, or one year, whichever comes first.
3. Average change in anti-hypertensive medication [ Time Frame: from beginning of treatment to 3 months ]
   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

Eligibility Criteria

• Ages Eligible for Study: 14 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

1. "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).
2. There is no limit on number of prior therapies.
3. Age ≥14 years.

4. 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%

Contacts and Locations

Locations

United States, Ohio

Cleveland Clinic Pediatric and Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

Peter Anderson

Investigators

• Principal Investigator: Peter M Anderson, MD, PhD; Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

More Information

Publications of Results:

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.

Other Publications:

Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, Dolloff NG, Messaris E, Scata KA, Wang W, Zhou JY, Wu GS, El-Deiry WS. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013 Feb 6;5(171):171ra17. doi: 10.1126/scitranslmed.3004828.

Allen JE, Krigsfeld G, Patel L, Mayes PA, Dicker DT, Wu GS, El-Deiry WS. Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway. Mol Cancer. 2015 May 1;14:99. doi: 10.1186/s12943-015-0346-9.

Allen JE, Prabhu VV, Talekar M, van den Heuvel AP, Lim B, Dicker DT, Fritz JL, Beck A, El-Deiry WS. Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10. Cancer Res. 2015 Apr 15;75(8):1668-74. doi: 10.1158/0008-5472.CAN-14-2356. Epub 2015 Feb 13.

Allen JE, Kline CL, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, Lev A, Baumeister M, Zhou L, Lulla A, Stogniew M, Schalop L, Benes C, Kaufman HL, Pottorf RS, Nallaganchu BR, Olson GL, Al-Mulla F, Duvic M, Wu GS, Dicker DT, Talekar MK, Lim B, Elemento O, Oster W, Bertino J, Flaherty K, Wang ML, Borthakur G, Andreeff M, Stein M, El-Deiry WS. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget. 2016 Nov 8;7(45):74380-74392. doi: 10.18632/oncotarget.11814. Erratum In: Oncotarget. 2021 Oct 12;12(21):2231.

Hayes-Jordan AA, Ma X, Menegaz BA, Lamhamedi-Cherradi SE, Kingsley CV, Benson JA, Camacho PE, Ludwig JA, Lockworth CR, Garcia GE, Craig SL. Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor. Neoplasia. 2018 May;20(5):524-532. doi: 10.1016/j.neo.2018.02.006. Epub 2018 Apr 5.

Prabhu VV, Lulla AR, Madhukar NS, Ralff MD, Zhao D, Kline CLB, Van den Heuvel APJ, Lev A, Garnett MJ, McDermott U, Benes CH, Batchelor TT, Chi AS, Elemento O, Allen JE, El-Deiry WS. Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors. PLoS One. 2017 Aug 2;12(8):e0180541. doi: 10.1371/journal.pone.0180541. eCollection 2017.

Anderson PM, Hanna R. Defining Moments: Making Time for Virtual Visits and Catalyzing Better Cancer Care. Health Commun. 2020 May;35(6):787-791. doi: 10.1080/10410236.2019.1587695. Epub 2019 Mar 24.

• Responsible Party: Peter Anderson, Site Principal Investigator, Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT03034200
• Other Study ID Numbers: CASE2716
• First Posted: January 27, 2017
• Last Update Posted: December 5, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Peter Anderson, Case Comprehensive Cancer Center:

Pheochromocytoma-paraganglioma; ONC201

Additional relevant MeSH terms:

Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; TIC10 compound; Antineoplastic Agents