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Doxorubicin With or Without Sildenafil, With Analysis of Cardiac Markers

Primary Purpose

Breast Cancer, Gastrointestinal Cancer, Genitourinary Cancer

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Doxorubicin
Sildenafil
Sponsored by
Virginia Commonwealth University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Breast cancer, Gastrointestinal cancer, Genitourinary cancer, Sarcoma, Gynecologic cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with any malignancy that is deemed appropriate for treatment with a chemotherapy regimen incorporating a < 3-hour infusion of doxorubicin >= 40 mg/m^2/dose not more frequently than weekly; single agent doxorubicin and combination chemotherapy are allowed; the duration of treatment and the cumulative dose of doxorubicin are determined by the chemotherapy regimen chosen for treatment of each individual's disease and up to the discretion of the treating provider; prior doxorubicin-based regimen(s) allowed, unless the most recent prior doxorubicin-based regimen resulted in documented refractory disease
  • At least 30 days since last doxorubicin before initiation of current doxorubicin-based regimen
  • Performance status Eastern Cooperative Oncology Group (ECOG) equal to or less than 2
  • Life-expectancy > 1 year
  • Women of childbearing potential and men must agree to use a medically accepted form of birth control for the duration of study and for a minimum of 6 months after the last dose of doxorubicin
  • Ability to understand and the willingness to sign a written informed consent; a signed informed consent must be obtained prior to any study-specific procedures

Exclusion Criteria:

  • Known congestive heart failure (CHF) (active disease or history of)
  • Left ventricular ejection fraction less than 55%
  • Planned concurrent administration of other investigational agents
  • Planned subsequent therapy with a human epidermal growth factor receptor 2 (HER2)-directed treatments (trastuzumab, pertuzumab, trastuzumab emtansine [T-DM1]) or other anthracyclines besides doxorubicin
  • Swallowing or absorption problems that might interfere with oral bioavailability of sildenafil
  • Known hypersensitivity to doxorubicin, sildenafil or any component of either agent
  • Planned chronic nitrate or alpha blocker therapy
  • Exclude persons who require ongoing administration of STRONG cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and/or inducers; short periods of exposure to CYP3A4 inhibitors will be allowed (i.e., exposure to aprepitant for three days at the time of doxorubicin exposure)
  • Other relative contraindications to sildenafil as defined in the prescribing information:

    • Myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months
    • Coronary artery disease causing unstable angina
    • Resting hypotension (blood pressure [BP] < 90/50) or hypertension (BP > 170/110) despite appropriate treatment
    • Known retinitis pigmentosa
  • Persisting or anticipated toxicity from prior therapy that might confound attribution of on-study adverse events (AEs)
  • Pregnant or nursing
  • Known hearing loss
  • History of priapism when exposed to PDE5 inhibitors (sildenafil, vardenafil, tadalafil)
  • Other condition(s) that in the opinion of the investigator might compromise the objectives of the study

Sites / Locations

  • Virginia Commonwealth University/Massey Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Sildenafil + doxorubicin

Doxorubicin-based chemotherapy

Arm Description

Patients receive sildenafil citrate PO QD* beginning at least 2 days prior to scheduled first dose of doxorubicin hydrochloride and continuing until 2 weeks after last scheduled dose of doxorubicin hydrochloride. Patients also receive doxorubicin hydrochloride IV as clinically indicated and as prescribed by treating provider. NOTE: *Patients receive sildenafil citrate PO TID on days that doxorubicin hydrochloride is also administered.

Patients receive doxorubicin hydrochloride IV as clinically indicated and as prescribed by treating provider.

Outcomes

Primary Outcome Measures

Safety of concurrent sildenafil with doxorubicin-based chemotherapy
Sildenafil will be administered at least 7 days prior to scheduled first dose of doxorubicin and continue daily dosing through 2 weeks after last doxorubicin dose. Multiple biomarkers as candidate early markers of anthracycline-induced cardiotoxicity will be tested.
The difference in left ventricular ejection fraction (LVEF) between arms
A repeated measures analysis of variance (ANOVA) will be used to compare the LVEF between Arm 1 and Arm 2 over all visits. A pooled t-test will also be performed to determine the change in LVEF between first and last visits.

Secondary Outcome Measures

Comparison of candidate early markers of cardiac injury
The fluctuation in the levels of biomarkers including novel ultra sensitive troponins and BNP, as well as tissue doppler imaging studies with echocardiography will analyzed.

Full Information

First Posted
June 15, 2011
Last Updated
August 22, 2019
Sponsor
Virginia Commonwealth University
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1. Study Identification

Unique Protocol Identification Number
NCT01375699
Brief Title
Doxorubicin With or Without Sildenafil, With Analysis of Cardiac Markers
Official Title
Randomized Open-label Phase 1b Study of Doxorubicin-based Chemotherapy Regimens, With and Without Sildenafil, With Exploratory Analysis of Intermediate Cardiac Markers
Study Type
Interventional

2. Study Status

Record Verification Date
August 2019
Overall Recruitment Status
Completed
Study Start Date
August 11, 2011 (Actual)
Primary Completion Date
August 4, 2017 (Actual)
Study Completion Date
January 19, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Virginia Commonwealth University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Sildenafil increases the therapeutic effect of doxorubicin used as treatment for cancers of solid tumors through both an increase in anti-tumor effects and protection from cardiac toxicity.
Detailed Description
Definitive study of sildenafil enhancement of anthracycline anticancer effects and cardioprotection would require a randomized, placebo-controlled trial involving large numbers of patients and many years of follow-up. It is appropriate to demonstrate that concurrent administration of sildenafil and doxorubicin is safe and tolerable. Second, in definitive studies it might be helpful to incorporate early markers of cardiac injury in order to gain early insight into cardioprotective effects, but there are no such established markers. As a correlative study, multiple intermediate markers will be tested. In order to investigate these candidate markers it is appropriate to study patients receiving doxorubicin alone, as early markers of injury may not be apparent in patients treated with the combination. In order to accomplish these two goals the trial is a randomized trial involving a sildenafil/doxorubicin group and a doxorubicin group.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Gastrointestinal Cancer, Genitourinary Cancer, Sarcoma, Gynecologic Cancer
Keywords
Breast cancer, Gastrointestinal cancer, Genitourinary cancer, Sarcoma, Gynecologic cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sildenafil + doxorubicin
Arm Type
Experimental
Arm Description
Patients receive sildenafil citrate PO QD* beginning at least 2 days prior to scheduled first dose of doxorubicin hydrochloride and continuing until 2 weeks after last scheduled dose of doxorubicin hydrochloride. Patients also receive doxorubicin hydrochloride IV as clinically indicated and as prescribed by treating provider. NOTE: *Patients receive sildenafil citrate PO TID on days that doxorubicin hydrochloride is also administered.
Arm Title
Doxorubicin-based chemotherapy
Arm Type
Active Comparator
Arm Description
Patients receive doxorubicin hydrochloride IV as clinically indicated and as prescribed by treating provider.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
123127, Doxorubicin Hydrochloride, 3-Hydroxyacetyldaunorubicin Hydrochloride, Adriamycin Hydrochloride, ADM, Adriacin, Adriamycin
Intervention Description
As prescribed by treating provider.
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Other Intervention Name(s)
Viagra, Revatio, Sildenafil Citrate, 171599-83-0
Intervention Description
Given PO, by mouth
Primary Outcome Measure Information:
Title
Safety of concurrent sildenafil with doxorubicin-based chemotherapy
Description
Sildenafil will be administered at least 7 days prior to scheduled first dose of doxorubicin and continue daily dosing through 2 weeks after last doxorubicin dose. Multiple biomarkers as candidate early markers of anthracycline-induced cardiotoxicity will be tested.
Time Frame
25 months
Title
The difference in left ventricular ejection fraction (LVEF) between arms
Description
A repeated measures analysis of variance (ANOVA) will be used to compare the LVEF between Arm 1 and Arm 2 over all visits. A pooled t-test will also be performed to determine the change in LVEF between first and last visits.
Time Frame
4 years
Secondary Outcome Measure Information:
Title
Comparison of candidate early markers of cardiac injury
Description
The fluctuation in the levels of biomarkers including novel ultra sensitive troponins and BNP, as well as tissue doppler imaging studies with echocardiography will analyzed.
Time Frame
37 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with any malignancy that is deemed appropriate for treatment with a chemotherapy regimen incorporating a < 3-hour infusion of doxorubicin >= 40 mg/m^2/dose not more frequently than weekly; single agent doxorubicin and combination chemotherapy are allowed; the duration of treatment and the cumulative dose of doxorubicin are determined by the chemotherapy regimen chosen for treatment of each individual's disease and up to the discretion of the treating provider; prior doxorubicin-based regimen(s) allowed, unless the most recent prior doxorubicin-based regimen resulted in documented refractory disease At least 30 days since last doxorubicin before initiation of current doxorubicin-based regimen Performance status Eastern Cooperative Oncology Group (ECOG) equal to or less than 2 Life-expectancy > 1 year Women of childbearing potential and men must agree to use a medically accepted form of birth control for the duration of study and for a minimum of 6 months after the last dose of doxorubicin Ability to understand and the willingness to sign a written informed consent; a signed informed consent must be obtained prior to any study-specific procedures Exclusion Criteria: Known congestive heart failure (CHF) (active disease or history of) Left ventricular ejection fraction less than 55% Planned concurrent administration of other investigational agents Planned subsequent therapy with a human epidermal growth factor receptor 2 (HER2)-directed treatments (trastuzumab, pertuzumab, trastuzumab emtansine [T-DM1]) or other anthracyclines besides doxorubicin Swallowing or absorption problems that might interfere with oral bioavailability of sildenafil Known hypersensitivity to doxorubicin, sildenafil or any component of either agent Planned chronic nitrate or alpha blocker therapy Exclude persons who require ongoing administration of STRONG cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and/or inducers; short periods of exposure to CYP3A4 inhibitors will be allowed (i.e., exposure to aprepitant for three days at the time of doxorubicin exposure) Other relative contraindications to sildenafil as defined in the prescribing information: Myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months Coronary artery disease causing unstable angina Resting hypotension (blood pressure [BP] < 90/50) or hypertension (BP > 170/110) despite appropriate treatment Known retinitis pigmentosa Persisting or anticipated toxicity from prior therapy that might confound attribution of on-study adverse events (AEs) Pregnant or nursing Known hearing loss History of priapism when exposed to PDE5 inhibitors (sildenafil, vardenafil, tadalafil) Other condition(s) that in the opinion of the investigator might compromise the objectives of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew S. Poklepovic, MD
Organizational Affiliation
Massey Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Virginia Commonwealth University/Massey Cancer Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298-0037
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
30221011
Citation
Poklepovic A, Qu Y, Dickinson M, Kontos MC, Kmieciak M, Schultz E, Bandopadhyay D, Deng X, Kukreja RC. Randomized study of doxorubicin-based chemotherapy regimens, with and without sildenafil, with analysis of intermediate cardiac markers. Cardiooncology. 2018;4:7. doi: 10.1186/s40959-018-0033-2. Epub 2018 Aug 29.
Results Reference
result

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Doxorubicin With or Without Sildenafil, With Analysis of Cardiac Markers

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