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Richmond, Virginia 23298


Purpose:

This is a phase 1 study of sildenafil in combination with regorafenib in patients with progressive advanced solid tumors. A modified 3+3 dose escalation design will be conducted for the dose escalation of the treatment combination: additional patients will be enrolled at the MTD until a total of 12 patients have been treated at the MTD.


Study summary:

This study is a single-arm, open-label, phase 1 trial to determine the RP2D of the combination of regorafenib and sildenafil. Both study medications will be taken orally on days 1-21 of each 28-day cycle. Using a modified 3+3 dose escalation design, 3-6 patients with an advanced solid tumor will be enrolled at each dose level. Additional patients will be enrolled at the MTD until a total of 12 patients have been treated at the MTD. Eligible patients will have received available standard treatments. Patients with solid tumors for which regorafenib would be considered a standard treatment are eligible as long as regorafenib has not been previously administered. Blood samples will be collected for correlative studies including PK, PD, and CTCs. Tumor samples archived from a previous biopsy or surgery will also be collected for correlative studies.


Criteria:

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 RECIST v1.1 - 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 - 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 - 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 cytochrome P450, family 3, subfamily A, polypeptide 4 (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


NCT ID:

NCT02466802


Primary Contact:

Principal Investigator
Andrew S. Poklepovic, MD
Massey Cancer Center


Backup Contact:

N/A


Location Contact:

Richmond, Virginia 23298
United States



There is no listed contact information for this specific location.

Site Status: N/A


Data Source: ClinicalTrials.gov

Date Processed: November 18, 2019

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