Zotatifin And EIF4A Platinum Helix Inhibition In Resistant AdvancedTNBC

Zotatifin And EIF4A Platinum Helix Inhibition In Resistant AdvancedTNBC

To find the optimal (best) recommended dose of zotatifin and carboplatin to treat patients with metastatic or recurrent TNBC.

Primary Objectives To determine the optimal biologic dose (OBD) of zotatifin and carboplatin. The OBD will be determined using dose limiting toxicities (DLTs) and ORR.

Inclusion Criteria

1. Participants must have histologically confirmed malignancy that is metastatic or locally recurrent unresectable and for which standard curative or palliative measures do not exist or are no longer effective.

2. Participants must have histologically or cytologically confirmed non-IBC triple negative breast cancers, defined here as ER<1%, PR<1% and HER2 negative per ASCO CAP 2018 guideline and have received at least 2 lines of therapy during metastatic treatment, OR Inflammatory breast cancer (IBC) clinically confirmed (³25) and that is ER<10% and PR<10% without limits of previous line of therapy.

3. At least 1 week since prior chemotherapy or radiation therapy. At least 2 weeks since prior use of strong or moderate inhibitors or inducers of CYP3A4.

4. Age ≥18 years.

5. Has at least one measurable lesion per RECIST 1.1

6. ECOG performance status ≤ 2 (Karnofsky ≥ 60%,).

7. Participants must have adequate organ and marrow function as defined below:

   • absolute neutrophil count ≥ 1,000/mcL
   • hemoglobin >9 mg/dL
   • platelets ≥ 100,000/mcL
   • total bilirubin ≤ institutional upper limit of normal (ULN)
   • AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN; ≤ 5 × institutional ULN if confirmed liver metastasis and elevation is deemed to be directly due to metastasis.
   • Creatinine clearance ≥30 mL/min (measured by the Cockcroft-Gault equation*).

8. Ability to understand and the willingness to sign a written informed consent

9. Cognitively impaired subjects will not be enrolled in this study.

10. Negative serum pregnancy test within 72 hours of receiving the first dose of the study medication for women of childbearing potential as per institutional guidelines.

11. Subjects of childbearing potential must be willing to use highly effective birth control methods or be surgically sterile or abstain from heterosexual activity for the course of the study. Women must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. This includes all female participant s, between the onset of menses (as early as 8 years of age) and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following:

    • Postmenopausal (no menses in greater than or equal to 12 consecutive months).
    • History of hysterectomy or bilateral salpingo-oophorectomy.
    • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
    • History of bilateral tubal ligation or another surgical sterilization procedure.

12. Approved methods of birth control are as follows: Hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control.

13. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of all study drug administration.

Exclusion Criteria

1. Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) except for alopecia. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to [enrollment/Cycle 1 Day 1] and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, including: Chemotherapy-induced neuropathy, Fatigue, Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies which may include: Hypothyroidism/hyperthyroidism, Type I diabetes, Hyperglycemia, Adrenal insufficiency, Adrenalitis and Skin hypopigmentation (vitiligo)
2. Participants with a history of interstitial lung disease (past or current) or active, non-infectious pneumonitis.
3. Participants with active autoimmune disease requiring systemic immunosuppression with corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs within 2 years before the first dose of study treatment.
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin or zotatifin.
5. Participants with uncontrolled intercurrent illness. Medical history or complication considered inappropriate for participation in the study, or a serious physical or psychiatric disease, the risk of which may be increased by participation in the study in the investigator's opinion
6. Participants with active infections requiring systemic antibiotics or antifungal or antiviral treatment within 14 days of C1D1 study treatment.
7. Participants with known active Hepatitis B or Hepatitis C infection. Testing is required to establish eligibility. Active Hepatitis B infection is defined as a positive Hepatitis B surface antigen and positive Hepatitis B core antibody test. Active Hepatitis C infection is defined as a quantitative HCV-RNA test with results greater than the lower limit of detection of the assay.
8. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
9. Participant s with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
10. Participant s with known HIV infection, defined as positive for HIV1/2 antibodies. Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
11. Participant s with psychiatric illness/social situations that would limit compliance with study requirements.
12. Pregnant women are excluded from this study due to potential for teratogenic or abortifacient effects.
13. Participant s with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
14. Participant s with active brain metastasis if treatment is warranted. Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
15. Participant s with known leptomeningeal disease, defined as unequivocal imaging or cytology-proven disease.
16. Participant s with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participant s should be class 2B or better, and EF greater than 45% despite best supportive care.
17. Participant s with a history or presence of screening ECG test that is clinically significantly abnormal in the investigator's opinion. Participants with a prolonged Qtc interval > 480 milliseconds (corrected by Fridericia or Bazett formula are excluded, but medically-controlled arrhythmias are allowed.
18. Participants with a history of significant cardiac events within 6 months of C1D1. Significant cardiac events include baseline NYHA class III/IV cardiac disease, acute myocardial infarction, severe/unstable angina, cardiomyopathy, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, critical conduction delay, transient ischemic attack or pulmonary embolism.
19. Participants who are receiving any other investigational agents.