Clinical trial NCT03889795: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Advanced Pancreatic Cancer
Advanced Solid Tumor
Keywords: Pancreatic
Solid Tumor
Advanced Pancreatic Cancer
Dose Escalation
Maximum Tolerated Dose
Lead sponsor: University of Toledo
Sponsor class: OTHER
First posted: 2019-03-26
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: 3 Subjects per Cohort + 3 additional subjects in Expansion Cohort.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose and/or Recommended Dose within the tested C3 dose range
timeFrame: Up to one year
Secondary outcomes:
measure: Safety and Tolerability: Occurrence of treatment - emergent adverse events (TEAEs) and other abnormalities
timeFrame: Up to 2 years
measure: Efficacy (Disease Response)
timeFrame: Up to 2 years
measure: Assess BIRC5 levels of expression in tumor tissue
timeFrame: RNA and protein levels of expression at baseline and at 2 months after C3 treatment
measure: Assess molecular changes induced by C3 administration in the blood for biomarker sensitivity/resistance assessment
timeFrame: Baseline and at 2 months
Other outcomes:
Locations:
city: Toledo
country: United States
facility: University of Toledo, Eleanor N. Dana Cancer Center
state: Ohio
Study officials:
affiliation: University of Toledo
name: Danae Hamouda, MD
role: PRINCIPAL_INVESTIGATOR
References: