Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors
Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors
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.
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
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
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:
Contraindication to antiangiogenic agents, including:
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:
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