Crossover Evaluation of Effect of Atorvastatin on PK of Irinotecan in CRC Patients Receiving FOLFIRI

NCT01605344 | Withdrawn Phase 1 DMC

• 1 other identifier: LCCC 1127
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the effect of atorvastatin on the pharmacokinetic profile of irinotecan and SN-38. To further evaluate the safety of atorvastatin in combination with FOLFIRI. To further evaluate the safety and of irinotecan in combination with atorvastatin.

Conditions

Advanced Adenocarcinoma of the Colon or Rectum

Keywords

Advanced colon cancer; Advanced rectal cancer; Metastatic colon cancer; Metastatic rectal cancer; Lipitor; Atorvastatin; FOLFIRI

Outcome Measures

Primary Outcomes (1)

• Area under the plasma concentration versus time curve (AUC) of irinotecan.

  At the end of the screening period, eligible patients will be randomly assigned in a 1:1 ratio to receive atorvastatin prior to Day 1 of FOLFIRI (ARM A) or atorvastatin prior to Day 15 FOLFIRI (ARM B). Patients in ARM A must start atorvastatin within 28 days of randomization and patients in ARM B should receive FOLFIRI within 28 days of randomization; if not, the Investigator must be notified.

  Blood samples will be collected on day 1 and 15 of FOLFIRI prior to treatment with irinotecan (baseline), immediately following the end of the irinotecan infusion, and at 0.5, 1, 1.5, 2, 4, 6, and 24 hours following the end of the irinotecan infusion.

Secondary Outcomes (1)

• Area under the plasma concentration versus time curve (AUC) of SN-38.

  Blood samples will be collected on day 1 and 15 of FOLFIRI prior to treatment with irinotecan (baseline), immediately following the end of the irinotecan infusion, and at 0.5, 1, 1.5, 2, 4, 6, and 24 hours following the end of the irinotecan infusion.

Study Arms (2)

Arm A

EXPERIMENTAL

ARM A subjects will receive atorvastatin 20 mg orally once daily given for two weeks prior to FOLFIRI. The last dose of atorvastatin will be taken day 1 of FOLFIRI. ARM A will then receive no statin for the next 2 weeks. Patients will receive FOLFIRI infusion on day 1 and day 15. Blood samples will be collected at baseline and periodically through 24 hours on day 1 and 15 of FOLFIRI.

Drug: FOLFIRI.; Drug: Atorvastatin

Arm B

EXPERIMENTAL

ARM B subjects will receive no atorvastatin prior to day 1 of FOLFIRI. ARM B subjects will receive atorvastatin 20 mg orally once daily for two weeks prior to day 15 of FOLFIRI. The last dose of atorvastatin will be taken day 15 of FOLFIRI. Patients will receive FOLFIRI infusion on day 1 and day 15. Blood samples will be collected at baseline and periodically through 24 hours on day 1 and 15 of FOLFIRI.

Drug: FOLFIRI.; Drug: Atorvastatin

Interventions

FOLFIRI. DRUG

All patients will receive FOLFIRI infusion on day 1 and day 15.

Also known as: 5-fluorouracil + leucovorin + irinotecan

Arm A; Arm B

Atorvastatin DRUG

A subjects will receive atorvastatin 20 mg orally once daily given for two weeks starting on Day -14 during PERIOD ONE. ARM A will then receive no statin during PERIOD TWO. ARM B subjects will receive no atorvastatin during PERIOD ONE. ARM B subjects will receive atorvastatin 20 mg orally once daily for two weeks during PERIOD TWO (starting on Day 2). One cycle = 28 days.

Also known as: Lipitor

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years of age (no upper age limit)
• Histological or cytological documentation of adenocarcinoma of the colon or rectum, and patient scheduled to begin FOLFIRI for treatment of their metastatic disease
• 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
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• 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
• 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.
• Medical oncologist agrees that two week window is appropriate/safe prior to start of FOLFIRI for trial candidate.
• The subject is capable of understanding and complying with parameters as outlined in the protocol
• Signed, IRB-approved written informed consent

You may not qualify if:

• 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.
• 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.
• Patients will not be allowed to receive bevacizumab or EGFR inhibitors (cetuximab or panitumumab) for the duration of the study (1 cycle).
• Patients with baseline LDL ≤ 100 mg/dL who are not currently treated with statins
• 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
• 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).
• 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.
• History of Gilbert's syndrome
• Pernicious anemia or other anemias due to Vitamin B12 deficiency (due to potential masking of deficiency by leucovorin)
• Known Dihydropyrimidine dehydrogenase (DPD) deficiency
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI
• Any patients with a history of stroke or TIA within 6 months prior to study enrollment
• 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)
• Ongoing infection \> Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)
• Known history of human immunodeficiency virus (HIV) infection

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead

Study Sites (1)

University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Related Links

• Website for UNC Lineberger Comprehensive Cancer Center

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms

Interventions

IFL protocol; Fluorouracil; Leucovorin; Irinotecan; Atorvastatin

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Camptothecin; Alkaloids; Pyrroles; Azoles; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Autumn McRee, MD

  University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2012
• First Posted: May 24, 2012
• Study Start: April 1, 2012
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2014
• Last Updated: February 27, 2014

Record last verified: 2014-02

Locations

US (1)