This is a phase 1b/2 study to evaluate the safety and efficacy of metronomic combination
therapy in subjects with TNBC who have progressed on or after previous SoC chemotherapy.
Phase 2 will be based on Simon's two-stage optimal design.
Treatment will be administered in two phases, an induction and a maintenance phase, as
described below. Subjects will continue induction treatment for up to 1 year. Treatment in
the study will be discontinued if the subject experiences progressive disease (PD) or
unacceptable toxicity (not corrected with dose reduction), withdraws consent, or if the
Investigator feels it is no longer in the subject's best interest to continue treatment.
Those who have a complete response (CR) in the induction phase will enter the maintenance
phase of the study. Subjects who experience ongoing stable disease (SD) or an ongoing partial
response (PR) at 1 year may enter the maintenance phase at the Investigator's discretion.
Subjects may remain on the maintenance phase of the study for up to 1 year. Treatment will
continue in the maintenance phase until the subject experiences PD or unacceptable toxicity
(not corrected with dose reduction), withdraws consent, or if the Investigator feels it is no
longer in the subject's best interest to continue treatment. The maximum time on study
treatment, including both the induction and maintenance phases, is 2 years.
Inclusion Criteria:
1. Age ≥ 18 years old.
2. Able to understand and provide a signed informed consent that fulfills the relevant
IRB or Independent Ethics Committee (IEC) guidelines.
3. Histologically-confirmed metastatic or unresectable TNBC that has either progressed on
or after anthracycline-based chemotherapy (or other approved standard of care therapy)
or subject has refused anthracycline-based chemotherapy, or other taxane- and
platinum-based therapies. TNBC is defined as breast cancer that lacks estrogen
receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth
factor receptor 2 (HER2) overexpression and/or amplification.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
5. Have at least 1 measurable lesion of ≥ 1.0 cm.
6. Must have a recent formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimen
following the conclusion of the most recent anticancer treatment. If an historic
specimen is not available, the subject must be willing to undergo a biopsy during the
screening period, if considered safe by the Investigator. If safety concerns preclude
collection of a biopsy during the screening period, a tumor biopsy specimen collected
prior to the conclusion of the most recent anticancer treatment may be used.
7. Must be willing to provide blood samples prior to the start of treatment on this
study.
8. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of
treatment, if considered safe by the Investigator.
9. Ability to attend required study visits and return for adequate follow-up, as required
by this protocol.
10. Agreement to practice effective contraception for female subjects of child-bearing
potential and non-sterile males. Female subjects of child-bearing potential must agree
to use effective contraception for up to 1 year after completion of therapy, and
non-sterile male subjects must agree to use a condom for up to 4 months after
treatment. Effective contraception includes surgical sterilization (eg, vasectomy,
tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with
spermicide, intrauterine devices (IUDs), and abstinence.
Exclusion Criteria:
1. Serious uncontrolled concomitant disease that would contraindicate the use of the
investigational drug used in this study or that would put the subject at high risk for
treatment-related complications.
2. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's
disease, autoimmune disease associated with lymphoma).
3. History of organ transplant requiring immunosuppression.
4. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative
colitis).
5. Inadequate organ function, evidenced by the following laboratory results:
1. Absolute neutrophil count < 1000 cells/mm3.
2. Platelet count < 75,000 cells/mm3.
3. Uncorrectable grade 3 anemia (hemoglobin < 8 g/dL).
4. Total bilirubin greater than the upper limit of normal (ULN; unless the subject
has documented Gilbert's syndrome).
5. Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT])
> 2.5 × ULN (> 5 × ULN in subjects with liver metastases).
6. Alkaline phosphatase levels > 2.5 × ULN (> 5 × ULN in subjects with liver
metastases, or >10 × ULN in subjects with bone metastases).
7. Serum creatinine > 2.0 mg/dL or 177 μmol/L.
8. Serum anion gap > 16 mEq/L or arterial blood with pH < 7.3.
6. Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or
clinically significant (ie, active) cardiovascular disease, cerebrovascular
accident/stroke, or myocardial infarction within 6 months prior to first study
medication; unstable angina; congestive heart failure of New York Heart Association
grade 2 or higher; or serious cardiac arrhythmia requiring medication. Subjects with
uncontrolled hypertension should be medically managed on a stable regimen to control
hypertension prior to study entry.
7. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection
fraction (LVEF) 10% below the institution's lower limit of predicted normal.
8. Dyspnea at rest due to complications of advanced malignancy or other disease requiring
continuous oxygen therapy.
9. Positive results of screening test for human immunodeficiency virus (HIV).
10. Current chronic daily treatment (continuous for > 3 months) with systemic
corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone),
excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic
reaction or anaphylaxis in subjects who have known contrast allergies is allowed.
11. Known hypersensitivity to any component of the study medication(s).
12. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug
reaction with any of the study medications.
13. Concurrent or prior use of a strong cytochrome P450 (CYP)3A4 inhibitor (including
ketoconazole, itraconazole, posaconazole, clarithromycin, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, and grapefruit
products) or strong CYP3A4 inducers (including phenytoin, carbamazepine, rifampin,
rifabutin, rifapentin, phenobarbital, and St John's Wort) within 14 days before study
day 1.
14. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8
inducer (rifampin) within 14 days before study day 1.
15. Participation in an investigational drug study or history of receiving any
investigational treatment within 30 days prior to initiation of treatment on this
study, except for testosterone-lowering therapy in men with prostate cancer.
16. Assessed by the Investigator to be unable or unwilling to comply with the requirements
of the protocol.
17. Concurrent participation in any interventional clinical trial.
18. Pregnant and nursing women.
