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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01205503

Enrollment

Registered

2010-09-20

Start date

2010-09-30

Completion date

2015-04-30

Last updated

2016-02-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer, Non-Hodgkin's Lymphoma

Keywords

chemobrain, Oxidative Stress, Mesna

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.

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.

Interventions

DRUGMesna

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

DRUGSaline

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

DRUGDoxorubicin

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.

DRUGCyclophosphamide

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

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
TNF-alpha Levels in Patients Receiving Doxorubicin Containing Chemotherapy	prior to and 3 hours post doxorubicin and between cycles 1 and 2	Continuous Measure of TNF-alpha at the 4 time points outlined in the protocol for each group.

Secondary

Measure	Time frame	Description
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	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	prior to and 3 hours post doxorubicin and between cycles 1 and 2	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	prior to and 3 hours post doxorubicin and between cycles 1 and 2	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	prior to and 3 hours post doxorubicin and between cycles 1 and 2	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.

Countries

United States

Participant flow

Recruitment details

Patients were recruited at the University of Kentucky Markey Cancer Center in Lexington, Kentucky, USA between October 2010 and May 2012.

Participants by arm

Arm	Count
Cycle 1 Saline; Cycle 2 Mesna Saline infused over 15 minutes administered prior to and 3 hours post doxorubicin infusion (over 15 minutes) during 1st cycle, then Mesna administered (infused over 15 minutes, 360 mg/m2) prior to and 3 hours post doxorubicin infusion during 2nd cycle Mesna: Mesna: 360 mg/m2 in 50 mL normal saline (NS) on cycle 2, day 1. Infused over 15 minutes	16
Cycle 1 Mesna; Cycle 2 Saline Mesna administered (infused over 15 minutes, 360 mg/m2) prior to and 3 hours post doxorubicin infusion during 1st cycle, then Saline administered prior to and 3 hours post doxorubicin infusion (over 15 minutes) during 2nd cycle Mesna: Mesna: 360 mg/m2 in 50 mL normal saline (NS) on cycle 1, day 1. Infused over 15 minutes	16
Total	32

Baseline characteristics

Characteristic	Cycle 1 Saline; Cycle 2 Mesna	Cycle 1 Mesna; Cycle 2 Saline	Total
Age, Continuous	57.81 years STANDARD_DEVIATION 11.7	51.75 years STANDARD_DEVIATION 15.51	54.78 years STANDARD_DEVIATION 1.97
Body Surface Area (BSA)	2.01 m^2 STANDARD_DEVIATION 0.23	1.93 m^2 STANDARD_DEVIATION 0.26	1.97 m^2 STANDARD_DEVIATION 0.25
Cancer Diagnosis Breast	7 participants	6 participants	13 participants
Cancer Diagnosis Lymphoma	9 participants	10 participants	19 participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0- Fully Active	10 participants	8 participants	18 participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1- Restricted	6 participants	8 participants	14 participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants	16 Participants	32 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Log 3-nitrotyrosine (3NT)	-0.11 log(ng/mg protein) STANDARD_DEVIATION 0.26	-0.05 log(ng/mg protein) STANDARD_DEVIATION 0.16	-0.08 log(ng/mg protein) STANDARD_DEVIATION 0.21
Log interleukin (IL)-18	6.06 log(pg/ml) STANDARD_DEVIATION 0.93	6.16 log(pg/ml) STANDARD_DEVIATION 0.76	6.11 log(pg/ml) STANDARD_DEVIATION 0.84
Log Plasma 4-hydroxynonenal (HNE)	-0.31 log(pmol/mg) STANDARD_DEVIATION 0.22	-0.28 log(pmol/mg) STANDARD_DEVIATION 0.2	-0.29 log(pmol/mg) STANDARD_DEVIATION 0.21
Log Protein Carbonyl (PC)	4.39 log(nmol/mg protein) STANDARD_DEVIATION 0.34	4.33 log(nmol/mg protein) STANDARD_DEVIATION 0.38	4.36 log(nmol/mg protein) STANDARD_DEVIATION 0.36
log TNF Alpha	1.27 log(pg/ml) STANDARD_DEVIATION 1.11	1.30 log(pg/ml) STANDARD_DEVIATION 1.16	1.28 log(pg/ml) STANDARD_DEVIATION 1.12
log TNF receptor 1	7.29 log(pg/ml) STANDARD_DEVIATION 0.44	7.04 log(pg/ml) STANDARD_DEVIATION 0.46	7.17 log(pg/ml) STANDARD_DEVIATION 0.46
Log TNF Receptor 2	8.31 log(pg/ml) STANDARD_DEVIATION 0.68	8.15 log(pg/ml) STANDARD_DEVIATION 0.74	8.23 log(pg/ml) STANDARD_DEVIATION 0.71
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	3 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	14 Participants	13 Participants	27 Participants
Region of Enrollment United States	16 participants	16 participants	32 participants
Sex: Female, Male Female	12 Participants	7 Participants	19 Participants
Sex: Female, Male Male	4 Participants	9 Participants	13 Participants
Treatment Type AC, vincristine, and prednisone (CHOP)	9 participants	10 participants	19 participants
Treatment Type Doxorubicin and cyclophosphamide (AC)	6 participants	5 participants	11 participants
Treatment Type Doxorubicin, cyclophosphamide and docetaxel (TAC)	1 participants	1 participants	2 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	29 / 32	30 / 32
serious Total, serious adverse events	1 / 32	1 / 32