ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

NCT03394027 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 18003418-C-0034
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The new drug ONC201 have been shown to kill breast cancer and endometrial cancer cells in the laboratory. The exact mechanism of action is not completely clear yet, but the ONC201 destroys the mitochondria inside the cells. Blocking mitochondrial activity may kill tumor cells, which would shrink tumors. Researchers want to see if ONC201 helps shrink tumors of certain breast or endometrial cancers and if that effect is maintained. Objective: To see if ONC201 shrinks tumors with a lasting effect. Eligibility: Adults ages 18 and older who have metastatic breast cancer (hormone-positive or triple-negative) or metastatic endometrial cancers. Design: Participants will be screened with:

• Medical history
• Physical exam
• Heart, blood, and urine tests
• Computed tomography (CT) and bone scans
• Review of medical report and tumor sample
• Participants will have a tumor biopsy before starting treatment and after 5 weeks taking the study drug. A scan or ultrasound may be used to guide the biopsy. Patients will receive local anesthetic and a needle will remove a small piece of tumor.
• The study will be done in 28-day cycles. Every day 1 of each cycle participants will repeat most screening tests, will be seen by the physician and receive a supply of the study drug.
• Participants will take the study drug by mouth once every 7 days. They will keep a diary of when they take the drug and any side effects. During cycle 1, participants will get weekly calls to discuss their health and symptoms. Images will be repeated every 2 cycles to evaluate response to the treatment.

Conditions

Triple Negative Breast Cancer; Endometrial Cancer; Hormone Receptor Positive, HER2 Negative Breast Cancer

Keywords

Imipridones; TNBC; Metastatic; Male Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Cohort 1 - Progression-free Survival (PFS)

  PFS in participants with refractory, metastatic hormone receptor positive breast cancer. PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the diameters of target lesions. And the appearance of one or more new lesions.

  Every 8 weeks, while on the Trial. Participants were followed for an average of 8-10 weeks (up to 16 weeks).

• Cohort 2 - Overall Response Rate (ORR) (Complete Response (CR) + Partial Response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST)

  Overall response (Complete response (CR) + Partial Response (PR) of ONC201 in participants with metastatic triple negative breast cancer was measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions.

  Every 8 weeks, while on the Trial. Participants were followed for an average of 8-10 weeks (up to 16 weeks).

• Cohort 3 - Overall Response Rate (ORR) (Complete Response (CR) + Partial Response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST)

  Overall response (Complete response (CR) + Partial Response (PR) of ONC201 in participants with advanced or metastatic endometrial cancer was measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions.

  Every 8 weeks, while on the Trial. Participants were followed for an average of 8-10 weeks (up to 16 weeks).

Secondary Outcomes (4)

• Number of Serious and Non-serious Adverse Events Grade ≥1 in Cohorts 1, 2, and 3

  Date treatment consent signed to date off study, approximately 13 months and 28 days for cohort 1, 11 months and 12 days for cohort 2, and 34 months and 29 days for cohort 3.

• Cohort 1 - Overall Response Rate (Complete Response (CR) + Partial Response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST)

  Every 8 weeks, while on the Trial. Participants were followed for an average of 8-10 weeks (up to 16 weeks).

• Number of Participants in Cohorts 1, 2, and 3 With Clinical Benefit

  Every 8 weeks, while on the Trial. Participants were followed for an average of 8-10 weeks (up to 16 weeks).

• Cohorts 2 and 3 - Progression-free Survival (PFS)

  Every 8 weeks, while on treatment, up to 3 months

Other Outcomes (1)

• Here is the Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

  Date treatment consent signed to date off study, approximately 13 months and 28 days for cohort 1, 11 months and 12 days for cohort 2, and 34 months and 29 days for cohort 3.

Study Arms (1)

Arm 1-ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

EXPERIMENTAL

Single arm divided in three cohorts, each cohort with a different type of metastatic disease: estrogen receptor (ER) + breast cancer, triple negative breast cancer, and endometrial cancer

Drug: ONC201

Interventions

ONC201 DRUG

625 mg by mouth every 7 days; each cycle = 28 days. Patients will receive ONC201 as long as they derive clinical benefit or toxicity becomes impeditive.

Arm 1-ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed persistent or recurrent invasive metastatic hormone receptor positive, human epidermal growth factor receptor 2 (HER2) normal breast cancer for which standard curative measures do not exist or are no longer effective. Hormone receptor positive is defined as estrogen receptor (ER) positive greater than or equal to 10% by immunohistochemistry (IHC) and/or progesterone receptor (PR) positive greater than or equal to 10% by IHC.HER2 will be considered negative per American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines (HER2 test result as negative if a single test (or both tests) performed show: 1) IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within \>10% of the invasive tumor cells; 2) IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within less than or equal to 10% of the invasive tumor cells; or 3) ISH negative based on: a) Single-probe average HER2 copy number \<4.0 signals/cell or b) Dualprobe HER2/ chromosome enumeration probe 17 (CEP17) ratio \<2.0 with an average HER2 copy number \<4.0 signals/cell)and HER2 testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity.
• Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Patients must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies.
• Hormone receptor + breast cancer (HR+BC) patients must have received prior treatment with at least 2 lines of hormonal treatment (Selective estrogen receptor modulators (SERM), aromatase inhibitor (AI), or fulvestrant) and deemed ineligible for further hormonal therapy. Patients may have received prior chemotherapy and there is no limit to the number of prior chemotherapy.
• Age greater than or equal to18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper limit of normal (ULN), or measured creatinine clearance greater than or equal to 60 mL/min/1.
• Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than or equal to 3 X ULN and total bilirubin \< 1.5 X ULN, unless known diagnosis of Gilbert's syndrome, where bilirubin less than or equal to 5 mg/dL will be permitted. Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients have historical readings consistent with the definition of Gilbert's syndrome prior to entering study.
• Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or equal to 1,500/mm\^3 (greater than or equal to 1.5 X10\^6/L), platelet count greater than or equal to 75,000/mm\^3 (greater than or equal to 75 X10\^6/L), and hemoglobin greater than or equal to 9 mg/dL (transfusion to obtain hemoglobin greater than or equal to 9 mg/dL within 24 hours prior to dosing is allowed).
• Patients must be able to swallow oral medications (capsules) without chewing, breaking, crushing, opening or otherwise altering the product formulation.
• The effects of ONC201 on the developing human fetus are unknown. For this reason and because imipridone agents are known to be teratogenic, female patients must either be of non-reproductive potential (i.e., post-menopausal by history: greater than or equal to 60 years old and no menses for greater than or equal to 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry and agree to use contraception or abstinence during the study and for and for at least 4 weeks after the final dose of any study-related medications. Male patients must use at least two forms of contraception during the study and for at least 4 weeks after the final dose of any study-related medications or have a partner who is not of reproductive potential.
• Ability of subject to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin); other investigational agents within 3 weeks or a programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PDL1) agent within 4 weeks prior to first dose of study enrollment.
• Patients who have undergone radiotherapy within 4 weeks of first dose of study treatment.
• Patients with a history of another invasive malignancy within the last 3 years.
• Patients with symptomatic brain metastases or leptomeningeal involvement. Patients with asymptomatic or brain metastases that have been treated with radiation at least 4 weeks prior to first dose of study treatment are allowed.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to imipridones or other agents used in study.
• Patients with a mean corrected Q wave T wave (QT) interval by Fridericia (QTcF) interval of \> 500 msec or receiving therapeutic agents known to prolong the QT interval
• Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, tachyarrhythmias or bradycardia, history of congestive heart failure, or myocardial infarction or stroke in the previous 3 months will be excluded.
• Known history of gastrointestinal illnesses that would preclude the absorption of ONC201, which is an oral agent.
• Patients with bone metastases who have initiated denosumab or bisphosphonate therapy within 28 days prior to Cycle 1 Day 1.
• Pregnant women are excluded from this study because ONC201 has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201. These potential risks may also apply to other agents used in this study.
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ONC201.
• Patients who have known active Hepatitis B, or Hepatitis C infections.
• Patients must have histologically or cytologically confirmed persistent or recurrent invasive, metastatic triple negative breast cancer (TNBC) for which standard curative measures do not exist or are no longer effective. TNBC, defined as estrogen receptor (ER) negative (ER \< 10%), PR negative (PR \<10%). HER2 will be considered negative per ASCO-CAP guidelines (HER2 test result as negative if a single test (or both tests) performed show: 1) IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within \>10% of the invasive tumor cells; 2) IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within less than or equal to 10% of the invasive tumor cells; or 3) ISH negative based on: a) Single-probe average HER2 copy number \<4.0 signals/cell or b) Dual-probe HER2/CEP17 ratio \<2.0 with an average HER2 copy number \<4.0 signals/cell) and HER2 testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity.
• Patients must have received at least one line of prior chemotherapy in the metastatic setting.
• Patients must have measurable disease, per RECIST 1.1.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Greer YE, Lipkowitz S. TIC10/ONC201: a bend in the road to clinical development. Oncoscience. 2015 Feb 20;2(2):75-6. doi: 10.18632/oncoscience.133. eCollection 2015. No abstract available.

  PMID: 25859547 BACKGROUND

• Endo Greer Y, Lipkowitz S. ONC201: Stressing tumors to death. Sci Signal. 2016 Feb 16;9(415):fs1. doi: 10.1126/scisignal.aad7955.

  PMID: 26884598 BACKGROUND

• Stein MN, Bertino JR, Kaufman HL, Mayer T, Moss R, Silk A, Chan N, Malhotra J, Rodriguez L, Aisner J, Aiken RD, Haffty BG, DiPaola RS, Saunders T, Zloza A, Damare S, Beckett Y, Yu B, Najmi S, Gabel C, Dickerson S, Zheng L, El-Deiry WS, Allen JE, Stogniew M, Oster W, Mehnert JM. First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. Clin Cancer Res. 2017 Aug 1;23(15):4163-4169. doi: 10.1158/1078-0432.CCR-16-2658. Epub 2017 Mar 22.

  PMID: 28331050 BACKGROUND

• Atkins SLP, Greer YE, Jenkins S, Gatti-Mays ME, Houston N, Lee S, Lee MJ, Rastogi S, Sato N, Burks C, Annunziata CM, Lee JM, Nagashima K, Trepel JB, Lipkowitz S, Zimmer AS. A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma. Oncologist. 2023 Oct 3;28(10):919-e972. doi: 10.1093/oncolo/oyad164.

  PMID: 37279797 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Endometrial Neoplasms; Neoplasm Metastasis; Breast Neoplasms, Male

Interventions

TIC10 compound

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Stanley Lipkowitz
• Organization: National Cancer Institute

lipkowis@navmed.nci.nih.gov

240-760-6129

Study Officials

• Stanley Lipkowitz, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 5, 2018
• First Posted: January 9, 2018
• Study Start: January 17, 2018
• Primary Completion: March 18, 2021
• Study Completion: October 7, 2021
• Last Updated: August 23, 2022
• Results First Posted: January 12, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)