Study of Regorafenib and Sildenafil for Advanced Solid Tumors

Study Overview
=================
Brief 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.

Detailed Description
-----------------
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.

Official Title
-----------------
Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors

Conditions
-----------------
Solid Tumor

Intervention / Treatment
-----------------
* Drug: Regorafenib
* Drug: Sildenafil Citrate


Participation Criteria
=================
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 =< 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: regorafenib and sildenafil citrate<br>Patients receive regorafenib and sildenafil citrate by mouth every day (PO QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Regorafenib<br>* Combination of regorafenib and of sildenafil when given to patients with advanced solid tumors. Regorafenib Administration and Treatment Schedule. Regorafenib will be taken orally once daily for the first 21 days of each 28-day cycle. Regorafenib will not be taken on the last 7 days of each cycle. Patients will be instructed as follows: Take regorafenib once daily with a low fat meal that contains less than 30% fat. Take the regorafenib tablets at about the same time each day. Swallow the tablets whole.<br>* Other names: BAY 73-4506;Drug: Sildenafil Citrate<br>* Combination of regorafenib and of sildenafil when given to patients with advanced solid tumors.Sildenafil Administration and Treatment Schedule. Sildenafil will be taken orally once daily at the same time the regorafenib dose is taken for the first 21 days of each 28-day cycle. Sildenafil will not be taken on the last 7 days of each cycle.<br>* Other names: 171599-83-0;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the recommended phase 2 dose (RP2D) of the combination of regorafenib and of sildenafil when given to patients with advanced solid tumors. | Patients' treatment dosing level, dose modification, DLTs, and evaluability for DLTs will be listed and summarized by basic descriptive statistics (such as frequency and proportion). The MTD/RP2D will be found based on the Definitions of Dose-Limiting Toxicity, Maximum Tolerated Dose, and Recommended Phase 2 Dose. RP2D for the combination of regorafenib and sildenafil that is less than or the same as the MTD. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and toxicity of the regorafenib and sildenafil combination | Adverse events reported according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Adverse events (AEs) characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) to determine safety and toxicity of the combination of regorafenib and sildenafil. | Up to 30 days after completion of study treatment | 
| To explore the antitumor effects of the regorafenib and sildenafil combination | Tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) | Up to 30 days after completion of study treatment | 
| To determine the pre-treatment expression of phosphodiesterase type 5 (PDE5) in tumor samples | Pre-treatment PDE5 expression identified by immunohistochemistry using archived tumor tissue. Pre-treatment PDE5 expression identified by immunohistochemistry (IHC) using archived tumor tissue. | 12- 24 months | 
| To evaluate the impact of sildenafil on the pharmacokinetics of regorafenib | Regorafenib plasma concentration measured at a total of 6 time points: at baseline (pre-treatment) and at 5 time points in cycle 1. Plasma concentration of regorafenib measured at 6 time points: at baseline (pre-treatment) and in cycle 1 on day 1 (post-treatment), on day 15 (pre- and post-treatment), and on day 21 (pre- and post-treatment) | 12-24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Advanced