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Regorafenib and Sildenafil Citrate in Treating Patients with Advanced Solid Tumors

Trial Status: Complete

This phase I trial studies the side effects and best dose of regorafenib and sildenafil citrate in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Regorafenib and sildenafil citrate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving regorafenib with sildenafil citrate may work better in treating patients with advanced solid tumors.

Inclusion Criteria

  • Advanced solid tumor that has progressed during or after treatment with approved therapies or for which there is no standard effective therapy available * Note: patients with solid tumors for which regorafenib would be considered a standard treatment are eligible as long as regorafenib has not been previously administered
  • Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin > 9 g/dL (untransfused)
  • Creatinine =< 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance >= 60 mL/min
  • Proteinuria =< grade 1 (ie, =< 1+ [30 mg/dL] using a random urine sample or < 1.0 gm using a 24-hour sample) * Note: if urine sample indicates >= grade 2 proteinuria (ie, 2+ [100 mg/dL]), a 24-hour urine sample must be collected and tested; urine protein in the 24-hour sample must be < 1.0 gm/24 hours
  • Total bilirubin =< 1.5 x ULN for the laboratory * Exception: if a patient has documented Gilbert’s syndrome and a total bilirubin is > 1.5 x ULN, the total bilirubin requirement may be waived provided the direct bilirubin is within normal limits (WNL) for the laboratory
  • Aspartate aminotransferase (AST) =< 2.5 x ULN for the laboratory
  • Alanine aminotransferase (ALT) =< 2.5 x ULN for the laboratory
  • Alkaline phosphatase =< 2.5 x ULN for the laboratory (=< 5 x ULN for patients with cancer involving the liver and/or bone)
  • Non-hematologic toxicities from previous cancer therapies resolved to =< grade 1 except chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of regorafenib and sildenafil (eg, alopecia, changes in pigmentation, stable endocrinopathies)
  • International normalized ratio (INR) is =< 1.5
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN for the laboratory
  • Left ventricular ejection fraction (LVEF) assessed by echocardiogram within 3 months prior to initiation of study treatment indicates an LVEF of >= 50%
  • A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of age and has not had a hysterectomy, must have a documented negative serum pregnancy test within 7 days prior to initiating study treatment
  • A WCBP and a male patient with a partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of study treatment and for 2 months following completion of study treatment
  • Ability to understand and willingness to sign the consent form written in English * Note: the consent form must be signed prior to the conduct of any trial-specific procedure

Exclusion Criteria

  • Meningeal metastases or brain metastases that are symptomatic or untreated * Note: patients who are asymptomatic and have had post-treatment imaging that indicates stable brain disease are eligible; (patients with meningeal metastasis are not eligible even if stable following treatment); also, note that brain imaging is required within 8 weeks prior to initiation of study therapy
  • Any investigational agent within 4 weeks prior to initiating study treatment
  • Previous therapy with regorafenib
  • If sorafenib was previously administered, intolerance to sorafenib
  • Inability to swallow medication
  • Known or suspected malabsorption condition or obstruction; Note: Use of pancreatic enzyme supplements is allowed to control malabsorption
  • Contraindications to sildenafil including: * Known retinitis pigmentosa * History of priapism related to PDE5 inhibitors (eg, sildenafil, vardenafil, tadalafil) * Presence of nonmalignant hematologic disorders, such as sickle cell disease, that may increase the risk of priapism
  • Contraindication to antiangiogenic agents, including: * Serious non-healing wound, non-healing ulcer, or bone fracture * Major surgical procedure or significant traumatic injury within 4 weeks prior to initiating study treatment * Pulmonary hemorrhage/bleeding event >= grade 2 within 12 weeks prior to initiating study treatment * Any other hemorrhage/bleeding event >= grade 3 within 12 weeks prior to initiating study treatment
  • History of organ allograft including corneal transplant
  • Any documented history of thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism within 6 months prior to initiating study treatment * Note: patients with a tumor-associated thrombus of locally-involved vessels should not be excluded from participating in the study
  • Evidence of bleeding diathesis or coagulopathy
  • Resting systolic blood pressure (BP) < 100 mmHg
  • Hypertension defined as systolic BP >= 140 mmHg or diastolic BP >= 90 mmHg despite optimal medical management
  • Active or clinically significant cardiac disease including any of the following: * Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment * Myocardial infarction within 6 months prior to initiating study treatment * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers * New York Heart Association (NYHA) class III or IV congestive heart failure
  • Seizure disorder requiring medication
  • Serious (ie, >= grade 3) uncontrolled infection
  • Known human immunodeficiency virus (HIV) seropositivity * Note: HIV testing is not required
  • Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
  • Pleural effusion or ascites that causes respiratory compromise (ie, >= grade 2 dyspnea)
  • Untreated or metastatic pheochromocytoma
  • Planned ongoing treatment with other drugs thought to potentially have adverse interactions with either of the medications included in the study treatment, for example: * Alpha 1-blockers * Vasodilators, such as nitrates * Other PDE5 inhibitors, eg, vardenafil, tadalafil * Therapeutic anticoagulation with vitamin K antagonists (eg, warfarin), heparins and heparinoids, or direct thrombin inhibitors (DTIs) ** Note: prophylactic low-dose anticoagulation to maintain vascular access devices or low-dose daily aspirin for cardiac health is permitted * Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, roflumilast, pimecrolimus ** Note: administration of steroids as part of symptom management or for other supportive care purposes is permitted * STRONG CYP3A4 inhibitors and/or STRONG CYP3A4 inducers; ** Note: if such medications have been used, patients must have discontinued these agents >= 2 weeks prior to initiating study treatment
  • Pregnancy or breastfeeding
  • Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient’s risk or limit the patient’s adherence with study requirements


Virginia Commonwealth University / Massey Cancer Center
Contact: Andrew Poklepovic
Phone: 804-628-2321


I. To determine the recommended phase 2 dose (RP2D) of the combination of regorafenib and sildenafil citrate (sildenafil) when given to patients with advanced solid tumors.


I. To evaluate the safety and toxicity of the regorafenib and sildenafil combination.

II. To explore the antitumor effects of the regorafenib and sildenafil combination.

III. To determine the pre-treatment expression of phosphodiesterase-5 (PDE5) in tumor samples.

IV. To evaluate the impact of sildenafil on the pharmacokinetics (PK) of regorafenib.


I. To explore the pharmacodynamic (PD) relationships between regorafenib and tumor response.

II. To assess the feasibility of isolating, enumerating, and analyzing circulating tumor cells (CTCs) to characterize cyclic guanosine monophosphate (cGMP) within tumor cells.

III. To assess the bioactivity of sildenafil in plasma.

IV. To assess the cytokine/growth factor levels in plasma.

OUTLINE: This is a dose escalation study of regorafenib and sildenafil citrate.

Patients receive regorafenib and sildenafil citrate orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Virginia Commonwealth University / Massey Cancer Center

Principal Investigator
Andrew Poklepovic

  • Primary ID MCC-13-09812
  • Secondary IDs NCI-2015-01101
  • ID NCT02466802