Study of Erlotinib and Metformin in Triple Negative Breast Cancer

Extended phase 1 trial of combined metformin and erlotinib in advanced triple negative breast cancer patients.

The goals of the study are to establish the maximum tolerated combined dosing of erlotinib and metformin as well as deciding if there is potential clinical utility of the combination in treating patients with triple negative breast cancer.

• Drug: Metformin
  Due to frequent GI upset in patients starting metformin the dose will be titrated up to the assigned dose level. The first metformin dose level will be 850 mg twice daily and be escalated to its maximum FDA approved dose of 850 mg three times daily. Dose escalation will follow the standard 3 + 3 design. Dose limiting toxicities will be determined during the first 5 weeks of therapy.
  Other Name: Glucophage
• Drug: Erlotinib
  Erlotinib dosing will start and remain at 150 mg daily.
  Other Name: Tarceva

Inclusion Criteria:

• Confirmed pathologic diagnosis of triple negative breast cancer, OR Prior diagnosis of ER or PR positive breast cancer [HER2 negative] that is demonstrated to be both ER and PR 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 material (see section 12.6).
• 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: 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: ANC ≥1,250/mm3, platelets ≥75,000/mm3, hemoglobin ≥8.5 g/dL, total bilirubin ≤1.5 x ULN, AST/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 registration.
• 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. Non-pregnant status will be determined in all women of childbearing potential.
• Patients must have signed an approved informed consent.

Exclusion Criteria:

• Active 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).

• Susan G. Komen Breast Cancer Foundation
• Astellas Pharma Inc