Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- To determine the recommended phase 2 dose (RP2D) of the combination of regorafenib and of sildenafil when given to patients with advanced solid tumors.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
A: regorafenib and sildenafil citrate
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.
干预措施: Regorafenib (Drug)
A: regorafenib and sildenafil citrate
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.
干预措施: Sildenafil Citrate (Drug)
结局指标
主要结局
To determine the recommended phase 2 dose (RP2D) of the combination of regorafenib and of sildenafil when given to patients with advanced solid tumors.
时间窗: 28 days
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.
次要结局
- To evaluate the safety and toxicity of the regorafenib and sildenafil combination(Up to 30 days after completion of study treatment)
- To explore the antitumor effects of the regorafenib and sildenafil combination(Up to 30 days after completion of study treatment)
- To determine the pre-treatment expression of phosphodiesterase type 5 (PDE5) in tumor samples(12- 24 months)
- To evaluate the impact of sildenafil on the pharmacokinetics of regorafenib(12-24 months)