Enalapril Maleate and Doxorubicin Hydrochloride in Treating Women With Breast Cancer

Overview

RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Enalapril maleate may help protect heart cells from the side effects of chemotherapy. It is not yet known whether giving enalapril maleate before or after doxorubicin hydrochloride is more effective in treating women with breast cancer. PURPOSE: This randomized clinical trial is studying giving enalapril maleate together with doxorubicin hydrochloride to see how well it works in treating women with breast cancer.

Full Title of Study: “The Effect of Enalapril on Doxorubicin Exposure in Adjuvant Breast Cancer Treatment”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2014

Detailed Description

This study is a drug interaction study designed to study the effects of enalapril on doxorubicin metabolism. Women with breast cancer for whom at least two cycles every 14 day doxorubicin is planned will be considered for enrollment. Study participation will be for 2 treatment cycles of doxorubicin or approximately 4 weeks. Patients will receive a 14 day course of daily enalapril in association with one cycle of doxorubicin and receive no study agent during the other cycle allowing patients to act as their own control. The sequence of enalapril dosing will be assigned by randomization at study enrollment. Blood samples for pharmacokinetics will be drawn before and at 7 time points after each of the two doses of doxorubicin. For each patient, serum doxorubicin and doxorubicinol concentrations both on and off of enalapril will be compared.

Interventions

  • Drug: doxorubicin hydrochloride
    • Given IV 5-10 minutes on day 1. Treatment repeats every 14 days for 2 courses in the absence of disease progression or unacceptable toxicity.
  • Drug: enalapril maleate
    • Given orally – Beginning 1 week before course 2, patients also receive oral enalapril maleate once daily until day 8 of course 2. OR Beginning 1 week before course 1, patients receive oral enalapril maleate once daily until day 8 of course 1.

Arms, Groups and Cohorts

  • Experimental: Doxorubicin alone first, then Doxorubicin with Enalapril
    • Patients receive doxorubicin hydrochloride IV over 5-10 minutes on day 1. Treatment repeats every 14 days for 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 1 week before course 2, patients also receive oral enalapril maleate once daily until day 8 of course 2.
  • Experimental: Doxorubicin with Enalapril first, then Doxorubicin alone
    • Patients receive doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 1 week before course 1, patients receive oral enalapril maleate once daily until day 8 of course 1.

Clinical Trial Outcome Measures

Primary Measures

  • Number of Patients With Doxorubicin Plasma Concentrations Demonstrating a Significant Increase or Decrease When Doxorubicin Was Given With Enalapril as Compared to When Doxorubicin Was Given Without Enalapril.
    • Time Frame: Baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion of doxorubicin
    • Doxorubicin plasma concentration (DPC) is the primary pharmacokinetic (PK) measure of the exposure. Each patient will have serial PKs performed twice – once with enalapril and once without enalapril. A mean increase or decrease of more than 115 ng/ml in DPC will be considered significant.

Secondary Measures

  • The Number of Participants With a Significant Increase or Decrease in the Baseline Levels of Btype Natriuretic Peptide, Cardiac Troponins, and Urine Microalbumin With or Without Enalapril
    • Time Frame: Baseline, 4, 24 and 48 hours after infusion of doxorubicin
    • Doxorubicin can induce changes in troponin, b-type natriuretic peptide and urine microalbumin. This analysis will determine whether enalapril prevents any of these changes. Statistical significance defined as a p < 0.05.
  • The Number of Participants With a Significant Increase or Decrease in Doxorubicin Hydrochloride Metabolite Levels With or Without Enalapril
    • Time Frame: Baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion of doxorubicin
    • Doxorubicin is metabolized to doxorubicinol. The effects of enalapril on doxorubicinol will be assessed. Statistical significance defined as a p < 0.05.

Participating in This Clinical Trial

Inclusion Criteria

  • Tissue diagnosis of a breast carcinoma – The oncologist must have prescribed doxorubicin as part of the planned chemotherapy regimen – Have acceptable organ function within 14 days of enrollment defined as: – liver function: total bilirubin, AST and ALT within normal institutional limits – kidney function: estimated Creatinine Clearance > 60 ml/min calculated creatinine clearance (for females) – formula: (140 – age) x weight x .85 divided by (sCr x 72) – At least 18 years old – Patient must have given written informed consent indicating an understanding of the investigational nature of the study – Agrees not to consume grapefruit juice while on the study Exclusion Criteria:

  • Known allergy to enalapril – Taking any known P450 cytochrome inducers or inhibitors – Taking any herbal supplements while on the study or the week prior to receiving doxorubicin – Taking an ace-inhibitor or angiotensin receptor blocker – Pregnant or lactating. Enalapril is Pregnancy Categories C (first trimester) and D (second and third trimesters)

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Masonic Cancer Center, University of Minnesota
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Anne H. Blaes, MD, Principal Investigator, Masonic Cancer Center, University of Minnesota

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