Breast cancer has several different subtypes based upon measurement of expression of proteins
found on the surface of the cancer cells. Cancers that lack expression of three of these
proteins, namely the estrogen receptor, progesterone receptor, and human epidermal growth
factor receptor 2 (HER2), are termed triple negative. By studying the molecular attributes of
breast cancer cells from a large group of breast cancer patients, a profile of markers
enriched in triple negative breast cancers (TNBC) was discovered. This profile includes loss
of expression of the protein, Phosphatase and Tensin homolog (PTEN), increased expression of
the protein, epidermal growth factor receptor (EGFR), and disruption of the cells ability to
repair DNA. These alterations also allow the tumor to thrive and likely evade treatment.
Observation has been made that the drug combination of metformin and erlotinib can inhibit
triple negative cells with these alterations. A clinical trial will be conducted to test the
ability of patients to tolerate the treatment (Phase I trial). This trial will be available
to triple negative breast cancer patients with metastatic disease. Other goals of the study
will be to confirm that the drugs are working properly and whether or not there are enough
responses to the treatment to warrant additional studies. If the treatment proves to be
effective, even if only in a subset of triple negative patients, future studies will focus on
validating biomarkers that can identify patients that will respond to the drug combination,
as well as discovering how cells become resistant to the treatment. The research has the
potential to advance a new effective treatment for a highly lethal disease and thus could
prolong patient survivals while maintaining a high quality of life.
- Confirmed pathologic diagnosis of triple negative breast cancer, OR Prior diagnosis of
ER or P-R positive breast cancer [HER2 negative] that is demonstrated to be both ER
and P-R negative (no or rare staining) on the patient's most recent biopsy.
- Patients with measurable or non-measurable metastatic disease (RECIST 1.1).
- At least one prior treatment for metastatic disease.
- Availability of adequate tumor tissue for exploratory analysis and plan to obtain the
- Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study. No chemotherapy or
radiotherapy may be given within 2 weeks prior to the start of protocol treatment.
- Patients must be ≥ 18 and < 80 years old.
- Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-2.
- Life expectancy of greater than 12 weeks.
- Patients must have recovered from uncontrolled intercurrent illness including, but not
limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris or cardiac arrhythmia.
- Required Laboratory Values: Absolute neutrophil count (ANC) ≥1,250/mm3, platelets
≥75,000/mm3, hemoglobin ≥8.5 g/dL, total bilirubin ≤1.5 x ULN, Aspartate
Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤3.0 x ULN, alkaline phosphatase
≤2.5 x ULN, Patients must have either a normal serum creatinine (<= IULN) OR estimated
creatinine clearance ≥ 60 ml/min (Cockcroft-Gault formula) within 14 days prior to
- Concomitant Medications: Erlotinib is primarily metabolized by CYP3A4. Patients CANNOT
be receiving enzyme-inducing or enzyme inhibiting agents listed here: Inhibitors:
Amiodarone, Amprenavir, Atazanavir, Chloramphenicol, Clarithromycin, Conivaptan,
Cyclosporine, Darunavir, Dasatinib, Delavirdine, Diltiazem, Erythromycin, Fluconazole,
Fluoxetine, Fluvoxamine, Fosamprenavir, Imatinib, Indinavir, Isoniazid, Itraconazole,
Ketoconazole, Lapatinib, Miconazole, Nefazodone, Nelfinavir, Posaconazole, Ritonavir,
Quinupristin, Saquinavir, Tamoxifen, Telithromycin, Troleandomycin, Verapamil,
Voriconazole. Inducers: Aminoglutethimide, Bexarotene, Bosentan, Carbamazepine,
Efavirenz, Fosphenytoin, Griseofulvin, Modafinil, Nafcillin, Nevirapine,
Oxcarbazepine, Phenobarbital, Phenytoin, Primidone, Rifabutin, Rifampin, Rifapentine,
St. John's wort, Sulfadimidine, Sulfinpyrazone, Troglitazone, Troleandomycin. All
concomitant medications must be recorded.
- Sexually Active Patients: For all sexually active patients, the use of adequate
contraception (hormonal or barrier method of birth control) will be required prior to
study entry and for the duration of study participation. The non-pregnant status will
be determined in all women of childbearing potential.
- Patients must have signed an approved informed consent.
- Active central nervous system (CNS) disease
a. Subjects with a history of CNS metastases or cord compression are allowable if they
have been clinically stable for at least 6 weeks since completion of definitive
treatment, are off steroids (if the steroids were part of the CNS disease treatment),
and in the case of brain metastases, have stable or improved imaging at least 6 weeks
after completion of their definitive treatment.
- Any serious medical or psychiatric illness that would prevent either the giving of
informed consent or the receipt of treatment.
- Patients pregnant or nursing.
- Patients who have used tobacco or nicotine products or medications within the last
three months given their significant effect on erlotinib drug levels.
- Diabetes. Defined as HgbA1C ≥ 6.5%.
- Prior metformin treatment OR EGFR targeted therapy.
- Rapidly progressive disease as judged by the investigator (Examples include rapidly
deteriorating performance status or symptomatic lymphangitic spread).
- Patient has any condition associated with increased risk of metformin-associated
lactic acidosis (e.g. congestive heart failure defined as New York Heart Association
(NYHA) Class III or IV functional status, history of acidosis of any type; habitual
intake of 3 or more alcoholic beverages per day).