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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Non-Hodgkin's Lymphoma
• Intervention / Treatment: Drug: Mesna; Drug: Saline; Drug: Doxorubicin; Drug: Cyclophosphamide

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Markey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cycle 1 Saline; Cycle 2 Mesna; Saline infused over 15 minutes administered prior to and 3 hours post doxorubicin infusion (over 15 minutes) with following Cyclophosphamide 6 hours post doxorubicin during 1st cycle, then Mesna administered (infused over 15 minutes, 360 mg/m2) prior to and 3 hours post doxorubicin infusion with following Cyclophosphamide 6 hours post doxorubicin during 2nd cycle	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; Other Names: Mesnex; Drug: Saline; Saline (used as a placebo) infused over the same time as mesna intervention; Other Names: Placebo; Drug: 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.; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2 IV over 30 minutes. Start 6 hours after doxorubicin started.; Other Names: Cytoxan; Endoxan; Cycloblastin; Neosar; Revimmune; Procytox
Other: Cycle 1 Mesna; Cycle 2 Saline; Mesna administered (infused over 15 minutes, 360 mg/m2) prior to and 3 hours post doxorubicin infusion with following Cyclophosphamide 6 hours post doxorubicin during 1st cycle, then Saline administered prior to and 3 hours post doxorubicin infusion (over 15 minutes) with following Cyclophosphamide 6 hours post doxorubicin during 2nd cycle	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; Other Names: Mesnex; Drug: Saline; Saline (used as a placebo) infused over the same time as mesna intervention; Other Names: Placebo; Drug: 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.; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2 IV over 30 minutes. Start 6 hours after doxorubicin started.; Other Names: Cytoxan; Endoxan; Cycloblastin; Neosar; Revimmune; Procytox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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

Collaborators and Investigators

• Sponsor: Mara Chambers
• Investigators: Principal Investigator: Mara Chambers, M.D., Markey Cancer Center

Publications and helpful links

General Publications

• 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-alpha and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study. PLoS One. 2015 Apr 24;10(4):e0124988. doi: 10.1371/journal.pone.0124988. eCollection 2015.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: September 17, 2010
• First Submitted That Met QC Criteria: September 17, 2010
• First Posted (Estimate): September 20, 2010

Study Record Updates

• Last Update Posted (Estimate): February 24, 2016
• Last Update Submitted That Met QC Criteria: January 27, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Oxidative Stress; Mesna; chemobrain
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Doxorubicin
• Other Study ID Numbers: 10-0431-F1V

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The de-identified data is already available as part of the published article supplement. PubMed Identification (ID) # 25909710