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

NCT01205503 | Completed Phase 2 Results DMC

• 1 other identifier: 10-0431-F1V
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Breast Cancer; Non-Hodgkin's Lymphoma

Keywords

chemobrain; Oxidative Stress; Mesna

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Protein Carbonyl Percent Changes From Baseline in Patients Receiving Doxorubicin Containing Chemotherapy

  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

  prior to and 3 hours post doxorubicin and between cycles 1 and 2

• Troponin Levels in Patients Receiving Doxorubicin Containing Chemotherapy

  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

  prior to and 3 hours post doxorubicin and between cycles 1 and 2

Study Arms (2)

Cycle 1 Saline; Cycle 2 Mesna

OTHER

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; Drug: Saline; Drug: Doxorubicin; Drug: Cyclophosphamide

Cycle 1 Mesna; Cycle 2 Saline

OTHER

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; Drug: Saline; Drug: Doxorubicin; Drug: Cyclophosphamide

Interventions

Mesna DRUG

Mesna: 360 mg/m2 in 50 mL normal saline (NS) either on cycle 2 or cycle 1, day 1. Infused over 15 minutes

Also known as: Mesnex

Cycle 1 Mesna; Cycle 2 Saline; Cycle 1 Saline; Cycle 2 Mesna

Saline DRUG

Saline (used as a placebo) infused over the same time as mesna intervention

Also known as: Placebo

Cycle 1 Mesna; Cycle 2 Saline; Cycle 1 Saline; Cycle 2 Mesna

Doxorubicin DRUG

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.

Also known as: Adriamycin

Cycle 1 Mesna; Cycle 2 Saline; Cycle 1 Saline; Cycle 2 Mesna

Cyclophosphamide DRUG

600 mg/m2 IV over 30 minutes. Start 6 hours after doxorubicin started.

Also known as: Endoxan, Cytoxan, Neosar, Procytox, Revimmune, Cycloblastin

Cycle 1 Mesna; Cycle 2 Saline; Cycle 1 Saline; Cycle 2 Mesna

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Mara Chambers: lead

Study Sites (1)

University of Kentucky Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Related 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-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.

  PMID: 25909710 RESULT

MeSH Terms

Conditions

Breast Neoplasms; Lymphoma, Non-Hodgkin; Chemotherapy-Related Cognitive Impairment

Interventions

Mesna; Sodium Chloride; Doxorubicin; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Limitations and Caveats

We did not measure any cognitive outcomes. We did not measure levels of anti-inflammatory cytokines, which could play a role in pathophysiology of Chemotherapy induced cognitive impairment (CICI). Small sample size, needs future trials to confirm.

Results Point of Contact

• Title: Emily Dressler, PhD
• Organization: Markey Cancer Center Biostatistics Shared Resource Facility

emilydressler@uky.edu

859 323-3076

Study Officials

• Mara Chambers, M.D.

  Markey Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 17, 2010
• First Posted: September 20, 2010
• Study Start: September 1, 2010
• Primary Completion: August 1, 2012
• Study Completion: April 1, 2015
• Last Updated: February 24, 2016
• Results First Posted: February 24, 2016

Record last verified: 2016-01

Data Sharing

• IPD Sharing: Will share

Locations

US (1)