study of regorafenib and sildenafil for advanced solid tumors

Conditions: Solid Tumor

Summary: 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.

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.

Eligibility 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 =\ = 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

Keywords: advanced