ONC201 With a Methionine-Restricted Diet in Patients With Metastatic Triple Negative Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well Akt/ERK inhibitor ONC201 (ONC201) with a methionine-restricted (MR) diet works in treating participants with triple negative breast cancer that has spread to other places in the body or cannot be removed by surgery. ONC201 activates a process that leads to the death of a cell. ONC201 is able to target tumor cells to get rid of them, but does not affect normal cells. MR diet is a methionine-free amino acid modified medical food. The addition of an intermittent MR diet may enhance the activity of ONC201. Giving ONC201 and an MR diet may work better in treating participants with breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine objective response rate (ORR) to ONC201 with a methionine-restricted diet in patients with metastatic triple negative breast cancer (TNBC). SECONDARY OBJECTIVES: I. To determine progression-free survival (PFS) to ONC201 with a methionine-restricted diet in patients with metastatic TNBC. II. To determine clinical benefit rate (complete or partial response plus stable disease) (CBR) at 4 months to ONC201 with a methionine-restricted diet in patients with metastatic TNBC. III. To determine overall survival (OS) to ONC201 with a methionine-restricted diet in patients with metastatic TNBC. IV. To assess metabolic indices in patients with metastatic TNBC treated with ONC201 and a methionine-restricted diet. V. To assess the expression of TRAIL receptor in circulating tumor cells (CTCs) prior, during and upon progression in patients with metastatic TNBC treated with ONC201 with a methionine-restricted diet. EXPLORATORY OBJECTIVES: I. To determine time to development of brain metastases or worsening of brain metastases in patients with metastatic TNBC treated with ONC201 with a methionine-restricted diet. STUDY DESIGN Patients with metastatic TNBC will be enrolled in a single-arm study evaluating ONC201 with a methionine-restricted diet. After completion of study treatment, participants are followed up every 3 months for 2 years.

Official Title
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ONC201 With a Methionine-Restricted Diet in Patients With Metastatic Triple Negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Akt/ERK Inhibitor ONC201
* Dietary Supplement: Methionine-Restricted Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic or unresectable TNBC (estrogen receptor [ER] < 10%, progesterone receptor [PR] < 10% and HER2 negative either by immunohistochemistry [IHC] or in situ hybridization method by American Society of Clinical Oncology [ASCO]-College of American Pathologists [CAP] guidelines). For patients with a previous tumor sample with positive ER, PR and/or HER2 results, if the most recent biopsy meets study criteria, they will be eligible. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. within 28 days prior to registration Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately Any number of prior lines of systemic therapy for metastatic disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Prior cancer treatment, including radiotherapy, must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen to =< grade 1 or to baseline prior to initiation of that therapy. Grade 2 or higher exceptions include alopecia, up to grade 2 neuropathy, and other grade 2 AEs or lab values not constituting a safety risk in the opinion of the treating physician. This criteria does not apply to lab tests for normal organ and marrow function outlined below. No active central nervous system (CNS) metastatic disease; subjects with prior definitive treatment of their CNS disease by surgical resection, stereotactic body radiation therapy (SBRT) or whole-brain radiotherapy (WBRT) > 28 days ago will be eligible if asymptomatic and off systemic steroids Life expectancy of greater than 12 weeks Normal organ and marrow function as defined per protocol definitions Absolute neutrophil count (ANC) > 1.5 x 10^3/uL Platelet count >= 100 x 10^3/uL Hemoglobin >= 9 g/dL Total bilirubin < 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 x ULN if participant has liver metastases, ≤5x ULN. Creatinine < ULN (institutional normal) Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are naturally postmenopausal for at least 12 consecutive months Females of childbearing potential must be willing to abstain from heterosexual activity or must agree to use adequate contraception (hormonal or barrier method) for the duration of study participation and for 90 days after discontinuation of study treatment Ability of the subject to understand and comply with study procedures for the entire length of the study Able to swallow ONC201 Be willing to discontinue vitamin and mineral supplements for the duration of the study if randomized to receive the methionine restricted diet Exclusion Criteria: No prior therapy with TRAIL receptor agonists Active infection requiring systemic therapy. Patients with a known history of human immunodeficiency virus (HIV) must have a CD4 count >= the institutional lower limit of normal within 28 days prior to registration. Patients with HIV must also be on a stable antiretroviral regimen for >= 28 days before registration Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study) Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three years Treatment with any investigational drug agent =< 14 days prior to registration or within 5 half-lives of that investigational product, whichever is longer Participant who has had major surgery =< 14 days prior to registration or has not recovered from major side effects of the surgery (tumor biopsy is not considered as major surgery) Known hypersensitivity to any of the excipients of ONC201 Any impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) Any concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate subject participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.) Participants who follow a vegan or vegetarian diet

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Akt/ERK inhibitor ONC201<br>Participants receive Akt/ERK inhibitor ONC201 PO on days 3, 10, and 17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Akt/ERK Inhibitor ONC201<br>* Given PO<br>* Other names: TIC10;|
| Experimental: Akt/ERK inhibitor ONC201, methionine-restricted diet<br>Participants receive Akt/ERK inhibitor ONC201 PO on days 3, 10, and 17. Participants also receive methionine-restricted diet PO on days 1-5, 8-12, and 15-19. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Akt/ERK Inhibitor ONC201<br>* Given PO<br>* Other names: TIC10;Dietary Supplement: Methionine-Restricted Diet<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) - Number of Participants Who Responded to Treatment | ORR will be estimated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, by dividing the total number of responders (complete plus partial responses plus CR or PR) or (CR or PR), respectively, by number of subjects with measurable disease and the exact 95% confidence interval will be provided. Due to early termination with few participants, only the counts of events have been reported. | maximum follow up time was 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) - Number of Participants With PFS | Will be summarized using Kaplan-Meier estimates of the median survival times. Point estimates as well as 95% confidence intervals will be provided. Due to early termination with few participants, only the counts of events have been reported. | maximum follow up time was 1 year | 
| Overall Survival (OS) - Number of Participants Who Survived the Study Period | Will be summarized using Kaplan-Meier estimates of the median survival times. Point estimates as well as 95% confidence intervals will be provided. Due to early termination with few participants, only the counts of events have been reported. | maximum follow up time was 1 year | 
| Clinical Benefit Rate (CBR) - Number of Participants Who Experienced Clinical Benefit | CBR will be estimated according to RECIST 1.1, by dividing the total number of responders (complete plus partial responses plus CR or PR or stable disease [SD]), by number of subjects with measurable disease and the exact 95% confidence interval will be provided. Due to early termination with few participants, only the counts of events have been reported. | At 4 months | 
| Duration of Response (DOR) | Will be measured using Kaplan-Meier methodology. A 95% confidence interval will be provided for the median duration of response. | Up to 2 years | 
| Incidence of Adverse Events - Number of Participants Who Experienced Adverse Events | Incidence of adverse events as measured by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Safety and tolerability will be assessed by frequency tables. Also, metabolic indices in patients with metastatic triple negative breast cancer (TNBC) treated with ONC-201 and a methionine-restricted diet will be assessed by frequency tables and descriptive statistics. | 30 days after last dose of study drug, up to 4 months on study |