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

Phase 2

Completed

Conditions: Hormone Receptor Positive, HER2 Negative Breast Cancer
Endometrial Cancer
Triple Negative Breast Cancer

Interventions: Drug: ONC201

Registration Number: NCT03394027

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: Background:

* Advanced breast cancer and endometrial cancer have limited treatment options. Current treatments provide a modest improvement in progression free survival, but no treatments improve survival.

* ONC201 is the founding member of a novel class of anticancer drugs called imipridones. The exact mechanism of ONC201 is unknown at this time, but preclinical data suggests that it causes global downregulation of mitochondrial genes leading to mitochondrial damage and ultimately non-apoptotic cell death.

* Preclinical studies have demonstrated that ONC201 selectively kills various cancer cells, including breast cancer cells (hormone-receptor positive cell lines, human epidermal growth factor receptor 2 (HER2+) cell line as well as triple negative breast cancer cell lines) and endometrial cancer cells, while having little effect on normal cells.

* An on-going phase I study of ONC201 has demonstrated clinical benefit in some solid tumors, including endometrial cancer.

Objectives:

* Cohort 1: To determine the progression free survival (PFS) at 8 months of ONC201 in metastatic hormone receptor positive breast cancer (HR+BC)

* Cohort 2: To determine the overall response rate (ORR) of ONC201 in metastatic triple negative breast cancer (TNBC)

* Cohort 3: To determine the overall response rate (ORR) of ONC201 in advanced endometrial cancer (EC)

Eligibility:

Selected Inclusion Criteria

* Histologically confirmed metastatic breast cancer or endometrial cancer with appropriate immunohistochemistry (IHC) testing and confirmation of HER2 non-amplification required for the breast cancer cohorts (cohorts 1 and 2)

* Age 18 years or older

* Female and male breast cancer patients are eligible for the breast cancer cohorts

* Eastern Cooperative Oncology Group (ECOG) 0 or 1

* Measurable metastatic disease with greater than or equal to 1 biopsiable lesion with willingness to undergo a biopsy

* Cohort 1 Hormone receptor + breast cancer (HR+BC) requires prior treatment with greater than or equal to 2 lines of hormonal treatment. No prior treatment required for cohorts 2/3 (TNBC and EC).

* Adequate hematopoietic, hepatic and renal function

Selected Exclusion Criteria

* 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 treatment.

* Radiotherapy less than or equal to 4 weeks before first dose of study treatment.

* Symptomatic central nervous system (CNS) metastases. Asymptomatic or brain metastases treated greater than 4 weeks from first dose of study treatment are allowed.

* History of invasive malignancy less than or equal to 3 years

* Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, tachyarrhythmias or bradycardia.

* History of congestive heart failure (CHF), or myocardial infarction (MI) or stroke in the previous 3 months will be excluded.

* Started denosumab or bisphosphonate therapy within 28 days prior to Cycle 1 Day 1

* Human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection

Design:

* This is a phase II single arm study of ONC201 divided in three cohorts, each cohort with different type of metastatic, advanced disease:

* Cohort 1: HR+ breast cancer (male and female)

* Cohort 2: Triple negative breast cancer (male and female)

* Cohort 3: Endometrial cancer (female only)

* All patients will receive ONC201 at the recommended phase 2 dose (RP2D) of 625mg by mouth every 7 days with each cycle being 28 days long. Patients will receive ONC201 as long as they derive clinical benefit or toxicity becomes impeditive

* Patients will be evaluated for toxicity every 4 weeks by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and for response every two cycles (8 weeks) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Cohort 1 - Progression-free Survival (PFS)	Every 8 weeks, while on the Trial. Participants were followed for an average of 8-10 weeks (up to 16 weeks).	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.
Cohort 2 - Overall Response Rate (ORR) (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).	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.
Cohort 3 - Overall Response Rate (ORR) (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).	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.

Secondary Outcome Measures

Name	Time	Method
Cohorts 2 and 3 - Progression-free Survival (PFS)	Every 8 weeks, while on treatment, up to 3 months	PFS in participants with triple negative breast cancer and endometrial 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.
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.	Serious and non-serious adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, , Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
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).	Overall response (Complete response (CR) + Partial Response (PR) of ONC201 in participants with refractory, metastatic hormone receptor positive 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.
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).	Clinical benefit is Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) 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. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (i.e., at least a 20% increase in the sum of the diameters of target lesions).