Clinical Trials /

ONC201 With and Without Methionine-Restricted Diet in Patients With Metastatic Triple Negative Breast Cancer

NCT03733119

Description:

This phase II trial studies how well Akt/ERK inhibitor ONC201 (ONC201) with or without 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ONC201 With and Without Methionine-Restricted Diet in Patients With Metastatic Triple Negative Breast Cancer
  • Official Title: ONC201 With and Without Methionine-Restricted Diet in Patients With Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: UW17107
  • SECONDARY ID: 2018-0252
  • SECONDARY ID: P30CA014520
  • NCT ID: NCT03733119

Conditions

  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
Akt/ERK Inhibitor ONC201ONC201, TIC10Arm A (Akt/ERK inhibitor ONC201)

Purpose

This phase II trial studies how well Akt/ERK inhibitor ONC201 (ONC201) with or without 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

      PRIMARY OBJECTIVES:

      I. To determine response rate to ONC201 with and without 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 and without a
      methionine-restricted diet in patients with metastatic TNBC.

      II. To determine clinical benefit rate (response rate plus stable disease) at 4- months to
      ONC201 with and without a methionine-restricted diet in patients with metastatic TNBC.

      III. To determine overall survival (OS) to ONC201 with and without a methionine-restricted
      diet in patients with metastatic TNBC.

      IV. To determine the safety of adding a methionine-restricted diet to ONC201 in patients with
      metastatic TNBC.

      V. To assess metabolic indices in patients with metastatic TNBC treated with ONC201 and a
      methionine-restricted diet.

      VI. 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 and
      without 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 and without a methionine-restricted
      diet.

      OUTLINE: Participants are randomized to 1 of 2 arms.

      ARM A: Participants receive Akt/ERK inhibitor ONC201 orally (PO) on days 3, 10, and 17.
      Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

      ARM B: 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.

      After completion of study treatment, participants are followed up every 3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (Akt/ERK inhibitor ONC201)ExperimentalParticipants 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.
  • Akt/ERK Inhibitor ONC201
Arm B (Akt/ERK inhibitor ONC201, methionine-restricted diet)ExperimentalParticipants 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.
  • Akt/ERK Inhibitor ONC201

Eligibility Criteria

        Inclusion Criteria:

          -  Metastatic or unresectable TNBC (estrogen receptor [ER] < 1%, progesterone receptor
             [PR] < 1% 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)

          -  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 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
             (other than alopecia) to =< grade 1 or to baseline prior to initiation of that
             therapy. Other than neuropathy, which must have resolved to =< grade 2

          -  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

          -  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) < 1.5 x 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), 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

        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

          -  Subject who has received radiotherapy =< 14 days prior to registration, and who has
             not recovered to grade 1 or better from related side effects of such therapy (except
             alopecia)

          -  Subject 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.)

          -  Patients who follow a vegan or vegetarian diet
      
Maximum Eligible Age:64 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using Kaplan-Meier estimates of the median survival times. Point estimates as well as 95% confidence intervals will be provided. PFS for the two treatment arms (Akt/ERK inhibitor ONC201 [ONC-201] alone versus [vs.] dietary methionine-restricted [MR] plus ONC-201) will be compared using the log-rank test.
Measure:Overall Survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using Kaplan-Meier estimates of the median survival times. Point estimates as well as 95% confidence intervals will be provided. OS for the two treatment arms (ONC-201 alone vs. dietary MR plus ONC-201) will be compared using the log-rank test.
Measure:Clinical Benefit Rate (CBR)
Time Frame:At 4 months
Safety Issue:
Description: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.
Measure:Duration of Response (DOR)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be measured using Kaplan-Meier methodology. A 95% confidence interval will be provided for the median duration of response.
Measure:Incidence of Adverse Events
Time Frame:Up to 30 days
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Wisconsin, Madison

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