Doxorubicin With or Without Sildenafil, With Analysis of Cardiac Markers

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.

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.

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