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Study participants will be offered metformin (850 mg twice a day), digoxin (0.25 mg once a day), and simvastatin (20 mg once a day) combination (C3) and Gemcitabine.

Study participants will be offered C3 only metformin (850 mg twice a day), digoxin (0.25 mg once a day), and simvastatin (20 mg once a day) combination (C3) if they decline Gemcitabine.

Combination treatment of Metformin, Simvastatin and Digoxin with Gemcitabine (Arm 1)

Gemcitabine and C3 (Metformin, Simvastatin, and Digoxin)

C3 only (Metformin, Simvastatin, and Digoxin) if patients decline Gemcitabine (Arm 2).

C3 (Metformin, Simvastatin, and Digoxin) only

Seema Chittalae, MD

Moro Salifu, MD

Mohan Preet, MD

Arjun Kandel, MD

The goals of this trial are: 1) To evaluate the safety and tolerability of C3 administration with Gemcitabine; and 2) To assess the disease response following C3 administration with Gemcitabine. The main question it aims to answer are: 1) Is C3 in combination with Gemcitabine safe, tolerable, and effective for reducing improving advanced stage pancreatic cancer? and 2) Can C3 in combination with Gemcitabine prolong the lives of patients with advanced stage pancreatic cancer. Participants will receive a combination of metformin (850 mg twice a day), digoxin (0.25 mg once a day), and simvastatin (20 mg once a day), also known as C3, and Gemcitabine (as per standard of care) for 2 years. If patients decline Gemcitabine, they will be offered the C3 medications only.

Background. Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers and ranks fourth in cancer-related deaths in the United States. It is among the 10 most commonly diagnosed cancers (9th in women and 10th in men), with approximately 56,770 new cases and 45,750 deaths in 2019. Current therapy for advanced disease includes the use of medications such as Gemcitabine, Erlotinib, Capecitabine, or combination treatments such as 5-fluorouracil, irinotecan, and oxaliplatin; or Gemcitabine and nab-paclitaxel. These standard of care medications have a survival advantage of less than six months in patients with advanced metastatic disease. Recent studies have shown that the use of metformin and simvastatin in 15,099 patients with pancreatic cancer significantly improved their survival.

Study Design/Methods. Based on those prior studies, the investigators will conduct an open-label, single-center, phase 2, feasibility trial of a combined metformin, digoxin, and simvastatin (C3) in 25 subjects with recurrent/refractory metastatic pancreatic cancer in order to evaluate their safety and tolerability. Patients who were previously treated for advanced pancreatic disease with no significant improvements in their disease, will be enrolled in this trial. C3 will be given as oral pills as described in recommended package insert safe levels in addition to their standard of care medication, Gemcitabine.

Study Interventions/Treatment Plan. The treatment plan is as follows: The first 3 patients enrolled in the study, will receive metformin (850 mg twice a day), digoxin (0.25 mg once a day), and simvastatin (20 mg once a day) for 28 days. If no toxic effects, the remaining 22 patients will be enrolled. Patients will be provided C3 medications every 28 days and will continue on the C3 medication for at least 2 years, or until death or recurrence/advancement of the disease. If more than one patient develops a toxic event, the dose will be reduced to metformin 850 mg/day, simvastatin 5 mg/day, and digoxin 0.0625 mg/day. If no further toxicities, then the remaining patients will receive the lower dose. If however, more than two patients develop a toxic event, then study discontinuation will be considered. If patients decline first line treatment (Gemcitabine), they will be offered a choice of C3 medications only.

Safety and Disease Response Assessments. During the conduct of the study, safety assessments will be conducted including physical examination, vital signs monitoring, performance status evaluation, blood CBC/serum chemistry, digoxin levels, toxicity assessment, and radiological tumor assessment. Disease response will be assessed using radiologic tumor assessments, and levels of biomarkers.

Objectives and Endpoints. The Primary Objectives are: 1) To evaluate the safety and tolerability of C3 administration with Gemcitabine. Endpoint and Outcome Measures: Adverse events and abnormalities in laboratory test values, markedly abnormal vital sign measurements; and 2) To assess disease response following C3 administration with Gemcitabine. Endpoint and Outcome Measures: Radiologic tumor assessment at baseline and quarterly thereafter. The Secondary Objectives are: 1) To assess levels of tumor biomarkers. Endpoint and Outcome Measures: Biomarker levels will be determined at baseline and at 2 months after C3 treatment; and 2) To assess molecular changes in biomarkers induced by C3 administration. Endpoint and Outcome Measures: Molecular expressions of tumor biomarkers such as BIRC5, CA19-9, and CEA at baseline, and 2 months after C3 treatment.

Given the safety profile of C3 in thousands of patients, the investigators anticipate that it will significantly improve the disease outcomes and prolong the lives of patients with metastatic advanced pancreatic cancer.

The treatment plan is as follows: The first 3 patients enrolled in the study, will receive metformin (850 mg twice a day), digoxin (0.25 mg once a day), and simvastatin (20 mg once a day) for 28 days. If no toxic effects, the remaining 22 patients will be enrolled. Patients will be provided C3 medications every 28 days and will continue on the C3 medication for at least 2 years, or until death or recurrence/advancement of the disease. If more than one patient develops a toxic event, the dose will be reduced to metformin 850 mg/day, simvastatin 5 mg/day, and digoxin 0.0625 mg/day. If no further toxicities, then the remaining patients will receive the lower dose. If however, more than two patients develop a toxic event, then study discontinuation will be considered. If patients decline first line therapy (Gemcitabine), they will be offered the choice of C3 medications only.

Phase 2A Pilot C3 Trial of Recurrent/Refractory Metastatic Advanced Pancreatic Cancer

Phase 2A Pilot Trial of Metformin, Digoxin, Simvastatin (C3) in Combination With Gemcitabine in Subjects With Recurrent / Refractory Metastatic Advanced Pancreatic Cancer

Data to be shared will include: patient demographics, vital signs, medical history, clinical laboratory tests, examination results, non-medication treatments (surgeries, procedures), physical examinations, and any adverse events related or unrelated to the investigational product, maximum tolerable dose (MTD), dose-limiting toxicities (DLT), all diagnoses, etc. All secondary outcomes (biomarkers, tumor size). All sensitive information will be secured using compliant encryption software and adequate physical security and operational controls. To de-identify the data, codes that participants will be removed from the data set and birth date will be converted to age to avoid "deductive disclosure" of participants. The Principal Investigator will make the final, de-identified, study data set and associated documentation available to the statistician. The study team will develop a data sharing agreement that provides for a commitment to using the data only for research purposes.

Number of participants with treatment-related Adverse Events as assessed by CTCAE v4.0

Tumor biomarkers as assessed by levels of BIRC5, CA19-9, CEA.

State University of New York - Downstate Medical Center

Oncologist

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 2A Pilot C3 Trial of Recurrent/Refractory Metastatic Advanced Pancreatic Cancer	NCT06030622	Pancreatic Canc...	Gemcitabine and... C3 (Metformin, ...	18 Years -	State University of New York - Downstate Medical Center
Phase 2A Pilot C3 Trial of Recurrent/Refractory Metastatic Advanced Pancreatic Cancer	NCT06030622	Pancreatic Canc...	Gemcitabine and... C3 (Metformin, ...	18 Years -	State University of New York - Downstate Medical Center
Phase 2A Pilot C3 Trial of Recurrent/Refractory Metastatic Advanced Pancreatic Cancer	NCT06030622	Pancreatic Canc...	Gemcitabine and... C3 (Metformin, ...	18 Years -	State University of New York - Downstate Medical Center

Spots Global Cancer Trial Database for c3 (metformin, simvastatin, and digoxin) only