Trial of Mesna to Prevent Doxorubicin-induced Plasma Protein Oxidation and Tumor Necrosis Factor Alpha (TNF-α) Release

Breast Cancer Clinical Trial

Official title:

Randomized, Blinded Trial of Mesna to Prevent Doxorubicin-induced Plasma Protein Oxidation and TNF-α Release

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01205503
• Other study ID #: 10-0431-F1V
• Status: Completed
• Phase: Phase 2
• First received: September 17, 2010
• Last updated: January 27, 2016
• Start date: September 2010
• Est. completion date: April 2015

Study information

• Verified date: January 2016
• Source: University of Kentucky
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether the drug mesna is able to block a series of chemical changes that occur in the blood of patients who receive the chemotherapy medicine doxorubicin. The researchers believe these blood chemical changes may the cause of "cloudy thinking" or "chemobrain" that are reported by some patients receiving chemotherapy.

Description:

Patients with lymphoma and breast cancer receiving chemotherapy regimens that include anthracycline drugs, such as doxorubicin, are at risk for developing cognitive and cardiac impairment. This potential cognitive impairment is refered to as "chemobrain" by some patients. We have demonstrated in mice that the drug mesna, which is used to prevent other complications of other chemotherapy drugs, prevents certain types of doxorubicin-induced damage of blood proteins. Blocking doxorubicin's damage of these blood proteins has blunted or prevented the subsequent markers of neurologic and cardiac injury in mice. This clinical trial will determine if mesna prevents doxorubicin-induced damage of blood proteins in cancer patients, and may establish if blood protein injury is the first step in anthracycline-induced cognitive and cardiac dysfunction and if using the drug mesna can blunt or prevent these changes in blood markers of injury for patients with cancer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: April 2015
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Participants must have histologically or cytologically confirmed breast cancer or non-hodgkin lymphoma and independent of protocol eligibility be determined to require one of the chemotherapy regimens listed below

Participants must require as standard-of-care treatment a chemotherapy regimen that includes one of the following combinations:

• doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2;

• doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2, and docetaxel 75 mg/m2;

• doxorubicin 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (capped at 2 mg dose), and prednisone 100 mg +/- rituximab 375 mg/m2

Age >18 years.Because these treatment regimens are rarely used in pediatric oncology, children are excluded from this study but will be eligible for future pediatric phase 2 trials.

Life expectancy of greater than 6 months.

Zubrod performance score 2 or better.

Patients must have normal organ and marrow function as defined below:

• leukocytes >3,000/microliter (mcL) (unless due to cancer in marrow)

• absolute neutrophil count >1,500/mcL (unless due to cancer in marrow)

• platelets >100,000/mcL (unless due to cancer in marrow)

• total bilirubin <1.5 X normal institutional limits

• Aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase (SGPT) <2.5 X institutional upper limit of normal

• creatinine within normal institutional limits OR

• creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal

• left ventricular function = 50 % ejection fraction

Because the standard of care chemotherapy agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

Patients may not be receiving any other investigational agents

Patients with known brain metastases should be excluded from this clinical trial because progressive neurologic dysfunction would confound the evaluation of neuro-cognitive outcomes.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to mesna or other agents used in the study (ie. sulfur containing drugs including "sulfa antibiotics" and celecoxib).

Patients requiring ongoing pharmacologic treatment of dementia are excluded.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Pregnant women are excluded from this study because the chemotherapy agents have known teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with chemotherapy, breastfeeding should be discontinued if the mother is treated with chemotherapy.

HIV-positivity is NOT a specific exclusion criteria.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Lymphoma, Non-Hodgkin
• Non-Hodgkin's Lymphoma

Intervention

Drug:
• Mesna
Mesna: 360 mg/m2 in 50 mL normal saline (NS) either on cycle 2 or cycle 1, day 1. Infused over 15 minutes
• Saline
Saline (used as a placebo) infused over the same time as mesna intervention
• Doxorubicin
60mg/m2 given IV over 15 minutes after receiving mesna or saline. Can allow for premedications of Ondansetron 8 mg orally, dexamethasone 12 mg orally, Aprepitant 125 mg orally.
• Cyclophosphamide
600 mg/m2 IV over 30 minutes. Start 6 hours after doxorubicin started.

Locations

Country	Name	City	State
United States	University of Kentucky Markey Cancer Center	Lexington	Kentucky

Sponsors (1)

Lead Sponsor	Collaborator
Mara Chambers

Country where clinical trial is conducted

United States, 

References & Publications (1)

Hayslip J, Dressler EV, Weiss H, Taylor TJ, Chambers M, Noel T, Miriyala S, Keeney JT, Ren X, Sultana R, Vore M, Butterfield DA, St Clair D, Moscow JA. Plasma TNF-a and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mes — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	TNF-alpha Levels in Patients Receiving Doxorubicin Containing Chemotherapy	Continuous Measure of TNF-alpha at the 4 time points outlined in the protocol for each group.	prior to and 3 hours post doxorubicin and between cycles 1 and 2	No
Secondary	Protein Carbonyl Percent Changes From Baseline in Patients Receiving Doxorubicin Containing Chemotherapy	Continuous Measure of percent changes from baseline of Protein Carbonyl at the 4 time points outlined in the protocol for each group. All measurements after naive baseline were adjusted as percent change from each individual's baseline measure.	prior to and 3 hours post doxorubicin and between cycles 1 and 2	No
Secondary	Plasma HNE Percent Changes From Baseline in Patients Receiving Doxorubicin Containing Chemotherapy	Continuous Measure of the percent change from baseline of Plasma HNE at the 4 time points outlined in the protocol for each group. All measurements after naive baseline were adjusted as percent change from each individual's baseline measure.	prior to and 3 hours post doxorubicin and between cycles 1 and 2	No
Secondary	Troponin Levels in Patients Receiving Doxorubicin Containing Chemotherapy	Continuous Measure of troponin at the 4 time points outlined in the protocol for each group.	prior to and 3 hours post doxorubicin and between cycles 1 and 2	No
Secondary	B-type Natriuretic Peptide (BNP) Blood Levels in Patients Receiving Doxorubicin Containing Chemotherapy	Continuous Measure of BNP at the 4 time points outlined in protocol for each of the groups. This is a 32-amino acid polypeptide secreted by heart ventricles in response to excessive stretching of cardiomyocytes.	prior to and 3 hours post doxorubicin and between cycles 1 and 2	No