Enalapril Maleate and Doxorubicin Hydrochloride in Treating Women With Breast Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Effect of Enalapril on Doxorubicin Exposure in Adjuvant Breast Cancer Treatment

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: enalapril maleate


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxorubicin alone first, then Doxorubicin with Enalapril<br>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. | Drug: doxorubicin hydrochloride<br>* 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.<br>* Other names: Adriamycin;Drug: enalapril maleate<br>* 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.<br>* Other names: Vasotec;|
| Experimental: Doxorubicin with Enalapril first, then Doxorubicin alone<br>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. | Drug: doxorubicin hydrochloride<br>* 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.<br>* Other names: Adriamycin;Drug: enalapril maleate<br>* 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.<br>* Other names: Vasotec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion of doxorubicin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline, 4, 24 and 48 hours after infusion of doxorubicin | 
| The Number of Participants With a Significant Increase or Decrease in Doxorubicin Hydrochloride Metabolite Levels With or Without Enalapril | Doxorubicin is metabolized to doxorubicinol. The effects of enalapril on doxorubicinol will be assessed. Statistical significance defined as a p < 0.05. | Baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion of doxorubicin | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer