A Prospective, Randomized, Crossover Evaluation of the Effect of Atorvastatin on the Pharmacokinetics of Irinotecan in Colorectal Cancer Patients Receiving FOLFIRI

Inclusion Criteria:

1. Age ≥18 years of age (no upper age limit)

2. Histological or cytological documentation of adenocarcinoma of the colon or rectum,
and patient scheduled to begin FOLFIRI for treatment of their metastatic disease

3. Patients taking statins at the time of enrollment are permitted. Patients taking
statins (or one of the prohibited drugs, see section 4.2.27 and section 12.1) must
agree to a 2 week washout prior to treatment with atorvastatin (see Schema) and
section 5.2

4. Life expectancy of at least 3 months

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤1

6. Adequate bone marrow, renal, and hepatic function, as evidenced by the following
within 7 days of treatment initiation with atorvastatin (or nothing, if enrolled into
Arm B): absolute neutrophil count (ANC) ≥1,500/mm3 platelets ≥100,000/mm3 hemoglobin
≥9.0 g/dL serum creatinine ≤1.5 x upper limit of normal (ULN) AST and ALT ≤ 3 x ULN
Total bilirubin ≤ 1.5 x ULN Alkaline phosphatase ≤2.5 x ULN Amylase and lipase ≤1.5 x
ULN INR/PTT ≤1.5 x ULN CPK ≤ ULN

7. Women of childbearing potential and male subjects must agree to use adequate
contraception for the duration of study participation. Adequate contraception is
defined as any medically recommended method (or combination of methods) as per
standard of care.

8. Medical oncologist agrees that two week window is appropriate/safe prior to start of
FOLFIRI for trial candidate.

9. The subject is capable of understanding and complying with parameters as outlined in
the protocol

10. Signed, IRB-approved written informed consent

Exclusion Criteria:

1. Any prior allergies to statin therapy or adverse events that precluded further use,
including but not limited to myopathy, rhabdomyolysis, etc. Patients who had to
change from atorvastatin to another statin for safety or efficacy reasons will also
be excluded.

2. Prior treatment with FOLFIRI or single agent irinotecan is prohibited within six
weeks of enrollment. All prior toxicity from previous irinotecan administration must
be resolved prior to enrollment. No more than 2 prior therapeutic regimens for
metastatic disease are allowed.

3. Patients will not be allowed to receive bevacizumab or EGFR inhibitors (cetuximab or
panitumumab) for the duration of the study (1 cycle).

4. Patients with baseline LDL ≤ 100 mg/dL who are not currently treated with statins

5. Patients homozygous for the UGT1A1*28 allele, and patients of Asian descent
homozygous or heterozygous for the UGT1A1*6 allele will be excluded due to their
altered irinotecan metabolism

6. Pregnant or breastfeeding patients. Women of childbearing potential must have a
pregnancy test performed a maximum of 7 days before start of atorvastatin and FOLFIRI
treatment, and a negative result must be documented before start of treatment with
atorvastatin or FOLFIRI (whichever is received first by patient).

7. Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤2 weeks prior to starting study drug. Erythropoietin
or darbepoetin therapy, if initiated ≥2 weeks prior to enrollment, may be continued.

8. History of Gilbert's syndrome

9. Pernicious anemia or other anemias due to Vitamin B12 deficiency (due to potential
masking of deficiency by leucovorin)

10. Known Dihydropyrimidine dehydrogenase (DPD) deficiency

11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
before start of Day 1 of treatment with FOLFIRI

12. Any patients with a history of stroke or TIA within 6 months prior to study
enrollment

13. Active cardiac disease including any of the following: Congestive heart failure (New
York Heart Association [NYHA]) ≥Class 2 (see Appendix C) Unstable angina (angina
symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial
infarction less than 6 months before start of Day 1 of FOLFIRI Cardiac arrhythmias
requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)

14. Ongoing infection > Grade 2 according to NCI Common Terminology Criteria for Adverse
Events version 4.0 (CTCAE v. 4.0)

15. Known history of human immunodeficiency virus (HIV) infection

16. Presence of acute or chronic liver disease, renal disease or pancreatitis

17. Known history of chronic hepatitis B or C

18. Symptomatic metastatic brain or meningeal tumors unless the patient is >6 months from
definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI
initiation, and is clinically stable with respect to the tumor at the time of study
entry. Also, the patient must not be undergoing acute steroid therapy or taper
(chronic steroid therapy is acceptable provided that the dose is s4.2.2table for one
month prior to D1 of treatment under this study)

19. History of organ allograft

20. Non-healing wound, ulcer, or bone fracture

21. Known hypersensitivity to any of the study drugs, study drug classes, or excipients
in the formulation

22. Inability to swallow oral medications

23. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4
within 4 weeks of start of FOLFIRI

24. Patients with diarrhea CTCAE v4 grade ≥2

25. Any malabsorption condition

26. Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior
therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which
must be ≤Grade 2)

27. Patients unable or unwilling to discontinue (and substitute if necessary) use of
prohibited drugs, juices and herbal supplements for at least 2 weeks prior to
atorvastatin initiation (see Appendix A for list of prohibited drugs, juices and
herbal supplements)

28. Substance abuse, medical, psychological, or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

29. Unwilling to provide consent for genetic studies of whole blood or plasma specimens