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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mara Chambers, University of Kentucky
ClinicalTrials.gov Identifier:
NCT01205503
First received: September 17, 2010
Last updated: January 27, 2016
Last verified: January 2016
  Purpose
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.

Condition Intervention Phase
Breast Cancer
Non-Hodgkin's Lymphoma
Drug: Mesna
Drug: Saline
Drug: Doxorubicin
Drug: Cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Blinded Trial of Mesna to Prevent Doxorubicin-induced Plasma Protein Oxidation and TNF-α Release

Resource links provided by NLM:


Further study details as provided by University of Kentucky:

Primary Outcome Measures:
  • TNF-alpha Levels in Patients Receiving Doxorubicin Containing Chemotherapy [ Time Frame: prior to and 3 hours post doxorubicin and between cycles 1 and 2 ] [ Designated as safety issue: No ]
    Continuous Measure of TNF-alpha at the 4 time points outlined in the protocol for each group.


Secondary Outcome Measures:
  • Protein Carbonyl Percent Changes From Baseline in Patients Receiving Doxorubicin Containing Chemotherapy [ Time Frame: prior to and 3 hours post doxorubicin and between cycles 1 and 2 ] [ Designated as safety issue: No ]
    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.

  • Plasma HNE Percent Changes From Baseline in Patients Receiving Doxorubicin Containing Chemotherapy [ Time Frame: prior to and 3 hours post doxorubicin and between cycles 1 and 2 ] [ Designated as safety issue: No ]
    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.

  • Troponin Levels in Patients Receiving Doxorubicin Containing Chemotherapy [ Time Frame: prior to and 3 hours post doxorubicin and between cycles 1 and 2 ] [ Designated as safety issue: No ]
    Continuous Measure of troponin at the 4 time points outlined in the protocol for each group.

  • B-type Natriuretic Peptide (BNP) Blood Levels in Patients Receiving Doxorubicin Containing Chemotherapy [ Time Frame: prior to and 3 hours post doxorubicin and between cycles 1 and 2 ] [ Designated as safety issue: No ]
    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.


Enrollment: 32
Study Start Date: September 2010
Study Completion Date: April 2015
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Mesnex
Drug: Saline
Saline (used as a placebo) infused over the same time as mesna intervention
Other Name: 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 Name: Adriamycin
Drug: Cyclophosphamide
600 mg/m2 IV over 30 minutes. Start 6 hours after doxorubicin started.
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • Cycloblastin
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 Name: Mesnex
Drug: Saline
Saline (used as a placebo) infused over the same time as mesna intervention
Other Name: 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 Name: Adriamycin
Drug: Cyclophosphamide
600 mg/m2 IV over 30 minutes. Start 6 hours after doxorubicin started.
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • Cycloblastin

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01205503

Locations
United States, Kentucky
University of Kentucky Markey Cancer Center
Lexington, Kentucky, United States, 40536
Sponsors and Collaborators
Mara Chambers
Investigators
Principal Investigator: Mara Chambers, M.D. Markey Cancer Center
  More Information

Publications:
Responsible Party: Mara Chambers, Principal Investigator, University of Kentucky
ClinicalTrials.gov Identifier: NCT01205503     History of Changes
Other Study ID Numbers: 10-0431-F1V 
Study First Received: September 17, 2010
Results First Received: September 18, 2015
Last Updated: January 27, 2016
Health Authority: United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: The de-identified data is already available as part of the published article supplement. PubMed Identification (ID) # 25909710

Keywords provided by University of Kentucky:
chemobrain
Oxidative Stress
Mesna

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Liposomal doxorubicin
Doxorubicin
Mesna
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protective Agents

ClinicalTrials.gov processed this record on September 27, 2016