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Phase IB Metformin, Digoxin, Simvastatin in Solid Tumors

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ClinicalTrials.gov Identifier: NCT03889795
Recruitment Status : Not yet recruiting
First Posted : March 26, 2019
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
John Nemunaitis, MD, University of Toledo Health Science Campus

Brief Summary:
This is a single-center trial in subjects with pancreatic cancer and other advanced solid tumors. It is an open-label, single arm dose escalation Phase IB trial with subjects accrued in a 3 subject dose escalation cohort. Subjects with treated advanced solid tumors, and showing disease progression on established standard therapy, will be enrolled in this trial.

Condition or disease Intervention/treatment Phase
Advanced Pancreatic Cancer Advanced Solid Tumor Drug: Metformin Drug: Simvastatin Drug: Digoxin Phase 1

Detailed Description:

This is a single-center trial in subjects with pancreatic cancer and other advanced solid tumors. It is an open-label, single arm dose escalation Phase IB trial with subjects accrued in a 3 subject dose escalation cohort. Subjects with treated advanced solid tumors, and showing disease progression on established standard therapy, will be enrolled in this trial.

C3 (Simvastatin + Digoxin + Metformin) will be given as three oral pills within recommended package insert safe levels. Subjects will be accrued in 3-subject dose escalation cohorts. 3 additional subjects will be treated at the presumptive maximum effective cohort dose/schedule for a total of 6 subjects at maximum effective level.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Sequential Assignment
Intervention Model Description: 3 Subjects per Cohort + 3 additional subjects in Expansion Cohort.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase IB Trial of Metformin, Digoxin, Simvastatin in Subjects With Advanced Pancreatic Cancer and Other Advanced Solid Tumors
Estimated Study Start Date : May 1, 2019
Estimated Primary Completion Date : May 1, 2020
Estimated Study Completion Date : May 1, 2022


Arm Intervention/treatment
Experimental: Dose Escalation
C3 (Metformin, Simvastatin and Digoxin) will be dosed each day of a 28 calendar day cycle. The starting dose level will be increased with each cohort. There are 3 cohorts. Upon reaching maximum tolerated dose, an expansion cohort will be opened. Cohort 1 - Metformin 850mg po/day, Simvastatin 5mg po/day, Digoxin 0.0625 mg po/day. Cohort 2 - Metformin 850 mg po/day for two weeks and 1,700 mg po/day for next two weeks, Simvastatin 20 mg po/day, Digoxin 0.25 mg po/day. Cohort 3 - Metformin 850 mg po/day for two weeks and 1,700 mg po/day for next two weeks, Simvastatin 40 mg po/day, Digoxin 0.25 mg po/day for two weeks and 0.50 mg po/day for next two weeks. Metformin to be taken at Dinner time, Simvastatin at Bed time and Digoxin in the Morning.
Drug: Metformin
Metformin oral pill will be taken daily in the evening.
Other Name: Glucophage

Drug: Simvastatin
Simvastatin oral pill will be taken daily in the evening.
Other Name: Zocor

Drug: Digoxin
Digoxin oral pill will be taken daily in the morning.
Other Name: Digitalis




Primary Outcome Measures :
  1. Maximum Tolerated Dose and/or Recommended Dose within the tested C3 dose range [ Time Frame: Up to one year ]
    Occurrence of any ≥ Grade 3 toxicity encountered within the four weeks following the administration of C3, regardless of attribution


Secondary Outcome Measures :
  1. Safety and Tolerability: Occurrence of treatment - emergent adverse events (TEAEs) and other abnormalities [ Time Frame: Up to 2 years ]
    Occurrence of treatment - emergent adverse events (TEAEs) and occurrence of abnormalities in laboratory test values, markedly abnormal vital sign measurements, and clinically significant abnormal electrocardiograms (ECGs), including conduction abnormalities and changes in QT interval

  2. Efficacy (Disease Response) [ Time Frame: Up to 2 years ]
    Response and progression evaluated using Response Evaluation criteria in solid tumors

  3. Assess BIRC5 levels of expression in tumor tissue [ Time Frame: RNA and protein levels of expression at baseline and at 2 months after C3 treatment ]
    Blood samples for pharmacokinetic analysis of C3 will be collected at designated time points.

  4. Assess molecular changes induced by C3 administration in the blood for biomarker sensitivity/resistance assessment [ Time Frame: Baseline and at 2 months ]
    Molecular signal tumor blood (plasma) and microenvironment protein expression patterns via quantitative mass spectrometry.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject ≥18 years with histologically confirmed solid tumor.
  2. Refractory or intolerant to established standard of care.
  3. Have at least one tumor mass amenable to core needle biopsy. Adequate Archival Tissue required for patients that will take part in the dose escalation cohorts.
  4. ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60%, or Lansky PS ≥60%.

4. Normal organ and marrow function: absolute granulocyte count ≥1,000/mm3, absolute lymphocyte count ≥400/mm3, platelets ≥100,000/mm3, total bilirubin ≤ institutional upper normal limit, AST/ASL ≤2x institutional upper limit of normal, GFR >60 mL/min/1.73 m2 and creatinine <1.5 mg/dL.

5. Normal pulmonary function defined as FEV1/FVC ≥70% 6. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to CTCAE Grade 2 or better.

7. If female of childbearing potential, has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a negative serum test will then be required for study entry.

8. Ability to understand and the willingness to sign a written informed protocol specific consent.

Exclusion Criteria:

  1. Anti-cancer chemotherapy, biologic therapy or immunotherapy within 3 weeks or radiation therapy within 2 weeks of first infusion.
  2. Known history of other malignancy unless having undergone curative intent therapy without evidence of that disease for ≥ 3 years except cutaneous squamous cell and basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other in situ cancers are allowed if definitively resected.
  3. Patients with PET non-avid disease.
  4. Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
  5. Known history of rhabdomyolysis.
  6. History of or current evidence of thrombosis.
  7. History of or current evidence of any condition (including medical, psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the Investigator.
  8. Known HIV or chronic Hepatitis B or C infection.
  9. Have signs and symptoms consistent with an active infection.
  10. Live vaccination for the prevention of infectious disease administered <30 days prior to the start of study therapy or inactivated vaccination <14 days prior to the start of study therapy.
  11. History of severe allergic, anaphylactic, or other hypersensitivity reactions to Metformin, Simvastatin, and/or Digoxin.
  12. Patients diagnosed with Wolff-Parkinson-White Syndrome or electrocardiographic (ECG) pattern.
  13. Women of childbearing potential who are found to be pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) or nursing.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03889795


Contacts
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Contact: Stephanie Smiddy, RN 419-383-4000 ext 6962 stephanie.smiddy@utoledo.edu

Locations
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United States, Ohio
University of Toledo, Eleanor N. Dana Cancer Center
Toledo, Ohio, United States, 43614
Sponsors and Collaborators
John Nemunaitis, MD
Investigators
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Principal Investigator: John J. Nemunaitis, MD University of Toledo

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Responsible Party: John Nemunaitis, MD, Principal Investigator and Medical Director, University of Toledo Health Science Campus
ClinicalTrials.gov Identifier: NCT03889795     History of Changes
Other Study ID Numbers: C3
First Posted: March 26, 2019    Key Record Dates
Last Update Posted: March 26, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by John Nemunaitis, MD, University of Toledo Health Science Campus:
Pancreatic
Solid Tumor
Advanced Pancreatic Cancer
Dose Escalation
Maximum Tolerated Dose

Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Metformin
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Simvastatin
Digoxin
Hypoglycemic Agents
Physiological Effects of Drugs
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Anti-Arrhythmia Agents
Cardiotonic Agents
Protective Agents