Clinical Trials /

Phase IB Metformin, Digoxin, Simvastatin in Solid Tumors

NCT03889795

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase IB Metformin, Digoxin, Simvastatin in Solid Tumors
  • Official Title: Phase IB Trial of Metformin, Digoxin, Simvastatin in Subjects With Advanced Pancreatic Cancer and Other Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: C3
  • NCT ID: NCT03889795

Conditions

  • Advanced Pancreatic Cancer
  • Advanced Solid Tumor

Interventions

DrugSynonymsArms
MetforminGlucophageDose Escalation
SimvastatinZocorDose Escalation
DigoxinDigitalisDose Escalation

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalC3 (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, 0.375 mg po/day for the next two weeks for cycle 1. Subjects will receive 0.50 mg po/day in Cohort 3, Cycle 2 and beyond. Metformin to be taken at Breakfast and Dinner time (as applicable), Simvastatin at Bed time and Digoxin in the Morning.
  • Metformin
  • Simvastatin
  • Digoxin

Eligibility Criteria

        Inclusion Criteria

          1. Subject ≥18 years with histologically confirmed solid tumor.

          2. Dose expansion subjects must have at least one tumor mass amenable to core needle
             biopsy.

          3. Refractory or intolerant to established standard of care.

          4. 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.

          5. ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60%, or Lansky PS ≥60%.

          6. 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.

          7. 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.

          8. 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.

          9. 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 only 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 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.

          7. Known HIV or chronic Hepatitis B or C infection.

          8. Have signs and symptoms consistent with an active infection.

          9. 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.

         10. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             Metformin, Simvastatin, and/or Digoxin.

         11. Patients diagnosed with Wolff-Parkinson-White Syndrome or electrocardiographic (ECG)
             pattern. Other cardiac conditions including: Previous MI with evidence of residual
             electrographic pattern consisted with bradycardia/heart block. Atrio-ventricular (AV)
             heart block (currently ongoing). History of ventricular fibrillation. Sick Sinus
             Syndrome or Sinus bradycardia thought to be caused by sinus node disease, unless
             effectively treated. Heart failure associated with preserved left ventricular ejection
             fraction, including constructive pericarditis, restrictive cardiomyopathy, and Amyloid
             heart muscle disease.

         12. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose and/or Recommended Dose within the tested C3 dose range
Time Frame:Up to one year
Safety Issue:
Description:Occurrence of any ≥ Grade 3 toxicity encountered within the four weeks following the administration of C3, regardless of attribution

Secondary Outcome Measures

Measure:Safety and Tolerability: Occurrence of treatment - emergent adverse events (TEAEs) and other abnormalities
Time Frame:Up to 2 years
Safety Issue:
Description: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
Measure:Efficacy (Disease Response)
Time Frame:Up to 2 years
Safety Issue:
Description:Response and progression evaluated using Response Evaluation criteria in solid tumors
Measure: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
Safety Issue:
Description:Blood samples for pharmacokinetic analysis of C3 will be collected at designated time points.
Measure:Assess molecular changes induced by C3 administration in the blood for biomarker sensitivity/resistance assessment
Time Frame:Baseline and at 2 months
Safety Issue:
Description:Molecular signal tumor blood (plasma) and microenvironment protein expression patterns via quantitative mass spectrometry.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:John Nemunaitis, MD

Trial Keywords

  • Pancreatic
  • Solid Tumor
  • Advanced Pancreatic Cancer
  • Dose Escalation
  • Maximum Tolerated Dose

Last Updated

August 28, 2019