S. F. Markowiak1, S. Liu1, J. Nemunaitis2, J. Austin3, R. Schimmoeller4, L. Hammerling4, F. C. Brunicardi1 1University Of Toledo Medical Center,Dept Of Surgery,Toledo, OH, USA 2University Of Toledo Medical Center,Dept Of Medicine,Toledo, OH, USA 3University Of Toledo Medical Center,College Of Pharmacy,Toledo, OH, USA 4Promedica Health Systems,Toledo Hospital,Toledo, OH, USA
Introduction: We screened an FDA approved drug library using a “pro-cancer” target gene BIRC5 super-promoter and identified a novel combination of metformin, simvastatin and digoxin, which suppressed expression of BIRC5 in cancer. In vivo testing of the combination of metformin, simvastatin and digoxin (C3) showed marked response in patient-derived PDAC cell-line mouse-model. A phase 1 protocol of the safety and response to C3 has been designed. Prior to trial initiation, safety assessment of 72 patients who received concurrent metformin, statin, and digoxin for non-cancer disorders was undertaken.
Methods: The ProMedica Health Systems database of 2.5 M patients was queried using Epic Systems® SlicerDicer for patients concurrently prescribed metformin, digoxin, and any statin. A matched, 2:1 cohort not taking these medications was identified for comparison. Each patient underwent extensive chart review for dosage, toxicity, adverse reactions, co-morbidities and cancer history. Safety data, including adverse reaction incidence, was compiled using Clinical Pharmacology© and the most recently published, FDA-approved package inserts. Independent samples t-test and X2 test were used.
Results: 72 consecutive patients (mean age 67-years, 44% female, 95% Caucasian) were observed for 18-months. 12.5% (n=9) expired during the observation period (n=7 cardiovascular, n=1 melanoma, n=1 unknown). The adverse drug reaction profile of the 72 patients was comparable to package insert criteria (p=0.999) and negative cohort (p=0.999) (see table 1). The average Modified Marshall Scoring System for Organ Failure of the 72 patients taking the three-drug combination was 0.7, revealing minimal toxicity. All patients took metformin once or twice daily for diabetes at an average of 652mg per dose. Digoxin was dosed every-other-day or daily at an average of 175mcg/dose, 54% for atrial fibrillation and 46% for CHF. For statins, 51.4% of patients took atorvastatin (n=37), 29.2% simvastatin (n=21), 16.7% pravastatin (n=12), and 2.8% lovastatin (n=2). There was no difference in mortality among the statins (p=0.280). 13 patients (18.1%) were long-term survivors of cancer: prostate (n=3), breast (n=5), colon (n=4), and bladder (n=1).
Conclusion: The combination of metformin, digoxin, and any statin (C3) taken concurrently over an 18-month period appears to confer no significant toxicity, as measured by Marshall Score and chart review for adverse drug reactions. Several unexpected long-term cancer survivors were identified in the cohort. Based upon these safety and toxicity data for patients taking C3 for advanced metastatic disease, we conclude that it would be safe to proceed with a phase 1 prospective trial using C3 for BIRC5-expressing cancer therapy.
