Single Agent ONC201 in Recurrent or Metastatic Endometrial Cancer

A Phase 2 Study of Single Agent ONC201 in Recurrent or Metastatic Endometrial Cancer

ONC201 is a small molecule which selectively targets the G protein-coupled receptor DRD2. Downstream of target engagement, ONC201 activates the integrated stress response (ISR) in tumor cell leading to inactivation of Akt and extracellular signal-regulated kinase (ERK) signaling as well as induction of the TRAIL pathway. ONC201 also inhibits dopamine receptor 2 (DRD2), resulting in anti-tumor responses in preclinical models. Single agent ONC201 has been examined in open-label Phase I studies in patients with advanced, treatment refractory solid malignancies. Due to its differential anti-proliferative and pro-apoptotic response in tumor cells, treatment was overall well tolerated, and the recommended phase II dose of ONC201 was set at 625mg every three weeks. An additional dose-escalation phase I study (NCT02609230) is further evaluating weekly versus three week dosing in patients with advanced solid tumors and multiple myeloma. Preliminary data from these phase I studies suggests a possible clinical benefit in patients with advanced, chemo-refractory endometrial cancers, with at least one mixed response noted in a patient with clear cell histology.

Hypothesis: Single agent ONC201 will demonstrate clinical benefit in women with recurrent or metastatic endometrial cancers, especially in those women with alterations in the Phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR) pathway.

Study Overview

• Status: Terminated
• Conditions: Endometrial Cancer
• Intervention / Treatment: Drug: ONC201

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have histologically confirmed metastatic or recurrent endometrial cancer. Eligible histologies include but are not limited to endometrioid, serous, clear cell, carcinosarcoma, adenosquamous, and mixed histologies.
2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1
3. Must have radiographic disease progression after 1 line of systemic cytotoxic therapy for metastatic disease or with progression within 12 months of completing adjuvant chemotherapy
4. Available archived tissue biopsies will be provided for correlative studies
5. Age > 18 years.
6. Eastern Cooperative Oncology group (ECOG) performance status of 0, 1, or 2

7. Patients must have adequate bone marrow, hepatic and renal function as defined below:

   • Leukocytes > 3,000/micro-liter (mcl)
   • Absolute neutrophil count > 1,500/mcL
   • Platelets > 100,000/mcL
   • Total bilirubin ≤1.5 upper limit of normal (ULN)
   • Aspartate aminotransferase/ Alanine aminotransferase (AST/ALT) < 2 ULN
   • Creatinine ≤1.5 ULN OR
   • Creatinine clearance > 60 Ml/min/1.73 m2 for patients with creatinine levels above ULN calculated using Calvert formula
8. Prior chemotherapy, hormonal and radiation therapy administered in the adjuvant setting will be allowed.
9. Life expectancy at least 3 months
10. Ability to understand and willingness to sign a written informed consent and HIPAA consent document
11. Patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment.

Exclusion Criteria:

1. No prior treatment with ONC201
2. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
3. The subjects who have not recovered to baseline or CTCAE ≤ Grade 1 from related toxicity to all prior therapies will be excluded. Patients with Non-serious adverse events such as alopecia, fatigue, weakness, loss of appetite and nausea that are non-significant will not be excluded.
4. Any other prior malignancy from which the patient has been disease free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site.
5. The subject is unable to swallow capsules
6. Patients receiving any other investigational agents
7. Patients with symptomatic brain metastases are excluded. Patients with asymptomatic and treated central nervous system (CNS) metastases may participate in this trial. The patient must have completed any prior treatment for CNS metastases > 28 days prior to study entry including radiotherapy or surgery. Steroids for the treatment of brain metastasis are not permitted, and patients must be stable off steroid treatment for 4 weeks prior to enrollment
8. Uncontrolled inter-current illness including, but not limited to ongoing or active infection. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
9. Active inflammatory gastrointestinal disease, chronic diarrhea (unless related to underlying malignancy or prior related treatment) or history of abdominal fistula, gastrointestinal perforation, peptic ulcer disease, or intra-abdominal abscess within 6 months prior to study enrollment. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed.
10. Known Human Immunodeficiency Virus (HIV)-positive patients on combination antiretroviral therapy
11. Known history of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection.
12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the patient inappropriate for entry into the study.
13. Pregnant or breast feeding. Refer to section 4.4 for further details.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ONC201 treatment Arm

Drug: ONC201; ONC201 will be administered at a dose of 625 mg by mouth weekly until disease progression, unacceptable toxicity, or if the patient discontinues for any other reason. Radiologic tumor assessment would be performed at baseline, Cycle 3 Day 1, Cycle 5 Day 1, and at the end of every 3 cycles beyond cycle 5. All patients including those removed from the study due to unacceptable toxicity, will undergo radiologic tumor assessment at the time of discontinuation (End of treatment).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) rate at 12 weeks	PFS will be calculated from the day of starting the treatment until 12 weeks	12 weeks
Objective Response rate (ORR) as determined by Response Criteria In Solid Tumors (RECIST)1.1 criteria	ORR will be calculated from the day of starting the treatment until disease progression	1-2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety profile of ONC201 will be determined by adverse events according to Common terminology criteria for Adverse Events (CTCAE) 4.03	Safety profile of ONC201 will be determined by type, frequency, severity and timing and relationship of Adverse Events and lab abnormalities to ONC201	1-2 years
Duration of response	Duration or response will be determined from the time when a partial or complete response is seen until disease progression	1-2 years
Duration of stable disease	Duration of stable disease will be calculated from the time of first treatment until disease progression	1-2 years
Median progression free survival	Progression free survival will be calculated from the time of the start of the treatment until disease progression	1-2 years

Collaborators and Investigators

• Sponsor: Fox Chase Cancer Center
• Collaborators: Oncoceutics, Inc.
• Investigators: Principal Investigator: Gina Mantia-Smaldone, MD, Fox Chase Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2017
• Primary Completion (Actual): September 9, 2020
• Study Completion (Actual): September 9, 2020

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (Actual): April 4, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 20, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Uterine Neoplasms; Endometrial Neoplasms; Antineoplastic Agents; TIC10 compound
• Other Study ID Numbers: GYN-106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No