Doxorubicin With or Without Sildenafil, With Analysis of Cardiac Markers

August 22, 2019 updated by: Virginia Commonwealth University

Randomized Open-label Phase 1b Study of Doxorubicin-based Chemotherapy Regimens, With and Without Sildenafil, With Exploratory Analysis of Intermediate Cardiac Markers

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Virginia
      • Richmond, Virginia, United States, 23298-0037
        • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sildenafil + doxorubicin

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.
Drug: Doxorubicin
As prescribed by treating provider.
Other Names:
  • Adriamycin
  • ADM
  • Adriacin
  • Adriamycin Hydrochloride
  • Doxorubicin Hydrochloride
  • 3-Hydroxyacetyldaunorubicin Hydrochloride
  • 123127
Drug: Sildenafil
Given PO, by mouth
Other Names:
  • Viagra
  • Revatio
  • Sildenafil Citrate
  • 171599-83-0
Active Comparator: Doxorubicin-based chemotherapy
Patients receive doxorubicin hydrochloride IV as clinically indicated and as prescribed by treating provider.
Drug: Doxorubicin
As prescribed by treating provider.
Other Names:
  • Adriamycin
  • ADM
  • Adriacin
  • Adriamycin Hydrochloride
  • Doxorubicin Hydrochloride
  • 3-Hydroxyacetyldaunorubicin Hydrochloride
  • 123127

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety of concurrent sildenafil with doxorubicin-based chemotherapy
Time Frame: 25 months
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.
25 months
The difference in left ventricular ejection fraction (LVEF) between arms
Time Frame: 4 years
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.
4 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of candidate early markers of cardiac injury
Time Frame: 37 months
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.
37 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Virginia Commonwealth University

Investigators

  • Principal Investigator: Andrew S. Poklepovic, MD, Massey Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2011

Primary Completion (Actual)

August 4, 2017

Study Completion (Actual)

January 19, 2018

Study Registration Dates

First Submitted

June 15, 2011

First Submitted That Met QC Criteria

June 16, 2011

First Posted (Estimate)

June 17, 2011

Study Record Updates

Last Update Posted (Actual)

August 26, 2019

Last Update Submitted That Met QC Criteria

August 22, 2019

Last Verified

August 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MCC-13419
  • NCI-2011-0098 (Registry Identifier: CTRP)

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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