- Adult (≥ 18 years of age).
- Histologically confirmed stage IV (metastatic) breast cancer.
- Participants must have biopsy proven ER negative (ER-), PR negative (PR-), HER2
negative, invasive breast cancer, by AJCC 7th edition staging. ER, PR, and HER2
positivity would be determined per institutional (local) guidelines.
- Pre- and postmenopausal women are eligible.
- ECOG performance status = 0-1
- Measurable disease as per RECIST Version 1.1.
- Ability to understand and the willingness to sign a written informed consent document.
Patient has signed the Informed Consent (ICF) prior to any screening procedures being
performed and is able to comply with protocol requirements.
- At least 2 weeks beyond treatment (chemotherapy, targeted therapy, immunotherapy,
and/or radiation therapy) or major surgery and recovered from all acute toxicities
(adverse events from prior anti-cancer agents need to be grade 1 or lower; grade 2
alopecia or peripheral neuropathy is permitted).
- At least 2 weeks beyond corticosteroids (however, low dose corticosteroids <20 mg
prednisone or equivalent daily are permitted).
- Patient has adequate bone marrow and organ function as defined by the following
laboratory values at screening:
- Absolute neutrophil count ≥1.5 × 109/L
- Platelets ≥100 × 109/L
- Hemoglobin ≥10.0 g/dL
- INR ≤1.5
- creatinine clearance ≥60 mL/min
- In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) <2.5 x ULN. If the patient has liver metastases, ALT and
AST <5 x ULN
- Total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in patients with
well-documented Gilbert's Syndrome.
- Fasting plasma glucose <140 mg/dL / 7.7 mmol/L and Glycosylated Hemoglobin
(HbA1c) ≤ 8% (both criteria must be met).
- Participants who have had anti-cancer therapy including targeted therapy or
chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C)
prior to entering the study, or those who have not recovered from adverse events
(clinically significant grade 2 or higher adverse events; grade 2 alopecia or
peripheral neuropathy is permitted) due to prior anti-cancer agents.
- Participants who have received prior irinotecan or ADC backbone with SN-38 or
- Participants with progressive CNS metastatic disease. Patients with stable CNS
metastasis would be eligible, provided mets radiologically stable for at least one
month, and patient is not actively taking steroids (more than 20 mg of prednisone or
- Current use of strong CYP3A inhibitors/inducers, or P-gp inhibitors within 7 days
prior to randomization. For a list of strong CYP3A inhibitors/inducers and P-gp
inhibitors, refer to Appendix C.
- Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements. Patient has 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).
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality including any of the following:
- History of angina pectoris, symptomatic pericarditis, coronary artery bypass
graft (CABG) or myocardial infarction within 6 months prior to study entry.
- Documented cardiomyopathy.
- History of cardiac failure, significant/symptomatic bradycardia, Long QT
syndrome, family history of idiopathic sudden death or congenital long QT
syndrome or any of the following:
- Known risk to prolong the QT interval or induce Torsade's de Pointes.
- Uncorrected hypomagnesemia or hypokalemia.
- Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg.
- Bradycardia (heart rate <50 at rest), by ECG or pulse.
- On screening, inability to determine the QTcF interval on the ECG (i.e.:
unreadable or not interpretable) or QTcF >450 screening ECG.
- HIV-positive participants on combination antiretroviral therapy are ineligible. These
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.
- Pregnant women are excluded from this study because the safety of study medications is
not established in pregnant women.
- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, or fertile men, unless they are using highly effective methods of
contraception throughout the study and after study drug discontinuation (till 8 weeks
in women and six months in males, post-study). Male patient should not donate sperm
while on treatment and up to 6 months after last dose. Women are considered
post-menopausal and not of child bearing potential if they have had 12 months of
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential. Highly effective contraception methods include:
- Total abstinence when this is in line with the preferred and usual lifestyle of
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment
- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception.
- In case of use of oral contraception, women should have been stable on the same
pill for a minimum of 3 months before taking study treatment. Note: While oral
contraceptives are allowed, they should be used in conjunction with a barrier
method of contraception due to unknown effect of drug-drug interaction.