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.
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.
