Study of Regorafenib and Sildenafil for Advanced Solid Tumors

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.

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