Doxorubicin With or Without Sildenafil, With Analysis of Cardiac Markers

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Virginia Commonwealth University Identifier:
First received: June 15, 2011
Last updated: March 22, 2016
Last verified: March 2016
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.

Condition Intervention Phase
Breast Cancer
Gastrointestinal Cancer
Genitourinary Cancer
Gynecologic Cancer
Drug: Doxorubicin
Drug: Sildenafil
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Open Label Study of Doxorubicin-based Chemotherapy Regimens, With and Without Sildenafil, With Exploratory Analysis of Intermediate Cardiac Markers

Resource links provided by NLM:

Further study details as provided by Virginia Commonwealth University:

Primary Outcome Measures:
  • Safety of concurrent sildenafil with doxorubicin-based chemotherapy [ Time Frame: 25 months ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 37 months ] [ Designated as safety issue: No ]
    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.

Enrollment: 26
Study Start Date: August 2011
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil + doxorubicin
Sildenafil, 100 mg capsule, once daily at least 7 days prior to scheduled first dose of doxorubicin and continue daily dosing through 2 weeks from scheduled last doxorubicin dose.
Drug: Doxorubicin
As prescribed by treating provider
Drug: Sildenafil
100 mg capsule once daily at least 7 days prior to scheduled first dose of doxorubicin and continue daily dosing through 2 weeks from scheduled last doxorubicin dose
Other Name: Viagra, Revatio
Active Comparator: Doxorubicin-based chemotherapy
Doxorubicin-based therapy will commence and continue as clinically indicated and as prescribed by treating provider.
Drug: Doxorubicin
As prescribed by treating provider

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.

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

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/m2/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.
  • At least 30 days since last doxorubicin before initiation of current doxorubicin-based regimen
  • Life-expectancy > 1 year
  • ECOG performance status </= 2
  • 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.
  • Able 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 (active disease or history of)
  • Left ventricular ejection fraction less than 55%
  • Planned concurrent administration of other investigational agents
  • Planned subsequent therapy with a HER2-directed treatments (trastuzumab, pertuzumab, 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 CYP3A4 inhibitors and/or inducers. The reference list of CYP isozymes and classification of strong, moderate, and weak interactions is available through the FDA website (Tables 5 of website)
  • 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 (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
  • 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
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Please refer to this study by its identifier: NCT01375699

United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298-0037
Sponsors and Collaborators
Virginia Commonwealth University
Principal Investigator: Andrew S. Poklepovic, MD Virginia Commonwealth University
  More Information

Responsible Party: Virginia Commonwealth University Identifier: NCT01375699     History of Changes
Other Study ID Numbers: MCC-13419  NCI-2011-0098 
Study First Received: June 15, 2011
Last Updated: March 22, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by Virginia Commonwealth University:
Breast cancer
Gastrointestinal cancer
Genitourinary cancer
Gynecologic cancer

Additional relevant MeSH terms:
Breast Neoplasms
Gastrointestinal Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Sildenafil Citrate
Liposomal doxorubicin
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors processed this record on August 24, 2016