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Phase IB Metformin, Digoxin, Simvastatin in Solid Tumors

Primary Purpose

Advanced Pancreatic Cancer, Advanced Solid Tumor

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Metformin
Simvastatin
Digoxin
Sponsored by
Danae Hamouda, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Pancreatic Cancer focused on measuring Pancreatic, Solid Tumor, Advanced Pancreatic Cancer, Dose Escalation, Maximum Tolerated Dose

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Toledo, Eleanor N. Dana Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dose Escalation

Arm Description

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, 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 once daily.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose and/or Recommended Dose within the tested C3 dose range
Occurrence of any ≥ Grade 3 toxicity encountered within the four weeks following the administration of C3, regardless of attribution

Secondary Outcome Measures

Safety and Tolerability: Occurrence of treatment - emergent adverse events (TEAEs) and other abnormalities
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
Efficacy (Disease Response)
Response and progression evaluated using Response Evaluation criteria in solid tumors
Assess BIRC5 levels of expression in tumor tissue
Blood samples for pharmacokinetic analysis of C3 will be collected at designated time points.
Assess molecular changes induced by C3 administration in the blood for biomarker sensitivity/resistance assessment
Molecular signal tumor blood (plasma) and microenvironment protein expression patterns via quantitative mass spectrometry.

Full Information

First Posted
March 19, 2019
Last Updated
August 29, 2023
Sponsor
Danae Hamouda, MD
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1. Study Identification

Unique Protocol Identification Number
NCT03889795
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 5, 2019 (Actual)
Primary Completion Date
December 30, 2024 (Anticipated)
Study Completion Date
December 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Danae Hamouda, MD

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Pancreatic Cancer, Advanced Solid Tumor
Keywords
Pancreatic, Solid Tumor, Advanced Pancreatic Cancer, Dose Escalation, Maximum Tolerated Dose

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
3 Subjects per Cohort + 3 additional subjects in Expansion Cohort.
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation
Arm Type
Experimental
Arm Description
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, 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 once daily.
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage
Intervention Description
Metformin oral pill will be taken daily at breakfast (cohort 1) and breakfast and dinner (cohort 2 and 3).
Intervention Type
Drug
Intervention Name(s)
Simvastatin
Other Intervention Name(s)
Zocor
Intervention Description
Simvastatin oral pill will be taken daily in the evening.
Intervention Type
Drug
Intervention Name(s)
Digoxin
Other Intervention Name(s)
Digitalis
Intervention Description
Digoxin oral pill will be taken once daily.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose and/or Recommended Dose within the tested C3 dose range
Description
Occurrence of any ≥ Grade 3 toxicity encountered within the four weeks following the administration of C3, regardless of attribution
Time Frame
Up to one year
Secondary Outcome Measure Information:
Title
Safety and Tolerability: Occurrence of treatment - emergent adverse events (TEAEs) and other abnormalities
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
Time Frame
Up to 2 years
Title
Efficacy (Disease Response)
Description
Response and progression evaluated using Response Evaluation criteria in solid tumors
Time Frame
Up to 2 years
Title
Assess BIRC5 levels of expression in tumor tissue
Description
Blood samples for pharmacokinetic analysis of C3 will be collected at designated time points.
Time Frame
RNA and protein levels of expression at baseline and at 2 months after C3 treatment
Title
Assess molecular changes induced by C3 administration in the blood for biomarker sensitivity/resistance assessment
Description
Molecular signal tumor blood (plasma) and microenvironment protein expression patterns via quantitative mass spectrometry.
Time Frame
Baseline and at 2 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Subject ≥18 years with histologically confirmed solid tumor. Dose expansion subjects must have at least one tumor mass amenable to core needle biopsy. Refractory or intolerant to established standard of care. 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. ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60%, or Lansky PS ≥60%. 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. 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. 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. Ability to understand and the willingness to sign a written informed protocol specific consent. Exclusion Criteria: Anti-cancer chemotherapy, biologic therapy or immunotherapy within 3 weeks or radiation therapy within 2 weeks of first infusion. 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. Patients with only PET non-avid disease. Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months. Known history of rhabdomyolysis. 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. Known HIV or chronic Hepatitis B or C infection. Have signs and symptoms consistent with an active infection. 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. History of severe allergic, anaphylactic, or other hypersensitivity reactions to Metformin, Simvastatin, and/or Digoxin. 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Danielle Mockensturm
Phone
419-383-6925
Email
danielle.mockensturm@utoledo.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Danae Hamouda, MD
Organizational Affiliation
University of Toledo
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Toledo, Eleanor N. Dana Cancer Center
City
Toledo
State/Province
Ohio
ZIP/Postal Code
43614
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Danielle Mockensturm
Phone
419-383-6925
Email
danielle.mockensturm@utoledo.edu
First Name & Middle Initial & Last Name & Degree
Danae Hamouda, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Phase IB Metformin, Digoxin, Simvastatin in Solid Tumors

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