Breast Cancer
Conditions
Keywords
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer
Brief summary
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
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
DRUGdoxorubicin 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.
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.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Patients who were randomized to receive either doxorubicin hydrochloride alone or doxorubicin hydrochloride with enalapril. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (14 Days) | Physician Decision | 0 | 1 |
| First Intervention (14 Days) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 8 | 2 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
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.
Time frame: Baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion of doxorubicin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxorubicin Hydrochloride Alone | 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. | 0 participants |
| Doxorubicin Hydrochloride With Enalapril | 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. | 0 participants |
Secondary
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.
Time frame: Baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion of doxorubicin
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Doxorubicin Hydrochloride Alone | The Number of Participants With a Significant Increase or Decrease in Doxorubicin Hydrochloride Metabolite Levels With or Without Enalapril | 0 Participants |
| Doxorubicin Hydrochloride With Enalapril | The Number of Participants With a Significant Increase or Decrease in Doxorubicin Hydrochloride Metabolite Levels With or Without Enalapril | 0 Participants |
Secondary
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.
Time frame: Baseline, 4, 24 and 48 hours after infusion of doxorubicin
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Doxorubicin Hydrochloride Alone | 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 | 0 Participants |
| Doxorubicin Hydrochloride With Enalapril | 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 | 0 Participants |