Phase I/II Study of Dasatinib in Combination With Zoledronic Acid for the Treatment of Breast Cancer With Bone Metastasis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 3
- 主要终点
- Objective Response in Bone From Time of Initiation of Therapy to > 6 Months
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of dasatinib and Zometa (zoledronic acid) that can be given in combination for the treatment of breast cancer that has spread to the bone. The safety and effectiveness of this combination will also be studied.
详细描述
The Study Drugs:
Zoledronic acid is designed to strengthen the bone and prevent fractures or breaks in the bone. Dasatinib is designed to block (stop) cells responsible for the breakdown of bone.
Study Groups:
If you are found to be eligible to take part in this study, you will be enrolled in a group of at least 3 participants to begin receiving zoledronic acid and dasatinib. The dose of dasatinib you receive will depend on when you enrolled in this study. All participants will receive the same amount of zoledronic acid. The first group of participants will be treated with the lowest dose of dasatinib given in combination with zoledronic acid.
Once the highest tolerable dose level is found, up to 25 additional participants will be enrolled at that dose level. This is called the Phase II portion of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 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
- •Patients must have a pathologically confirmed diagnosis of invasive carcinoma of the breast.
- •Patients must carry a diagnosis of metastatic breast cancer with predominant bone involvement. For the purposes of this study, predominant bone involvement will be defined as radiographically detected bone metastasis in the presence or absence of other sites of metastatic breast cancer (i.e. visceral involvement). If visceral involvement is present, patients must be asymptomatic and have no tumors in visceral organs that measure >3cm in size.
- •Patients must agree to serial urine collections for measurement of Ntx.
- •Age >/= 18 years.
- •Patients must be able to swallow oral medications. Dasatinib must be taken whole and cannot be crushed.
- •Patients must have evaluable disease using WHO Criteria for Assessment of Disease Response in Bone or MDACC Modified Response Criteria for Assessment of Disease Response in Bone.
- •Patients must not have had >1 chemotherapy regimens for metastatic disease. Patients with metastasis diagnosed </= 6 months after completion of adjuvant chemotherapy are considered to have had chemotherapy for metastatic breast cancer.
- •Patients with ER positive disease must have had disease progression on at least one prior hormonal therapy for metastatic disease. Patients must also have developed disease progression on their most recent hormonal therapy regimen and be agreeable to continue this regimen in combination with protocol therapy. For the purposes of this study disease progression while receiving hormonal therapy will be defined as: Radiographic evidence of progressive disease according to RECIST criteria, Progression of disease by physical exam in patients with skin involvement. Continued in # 9
- •Continuation from # 8: 25% increase in tumor marker as measured on two evaluations no less than 72 hours apart.
- •Patients must have and ECOG performance status of </=
- •Patients must not require concurrent radiation or chemotherapy while receiving protocol therapy.
- •Patients must not have an active infection requiring the use of intravenous antibiotics. The use of oral antibiotics as prophylaxis is allowed.
- •Patients must have a baseline ECG with QTc within the normal range within 28 days prior to registration.
- •Patients must be informed of the investigational nature of the study and must sign and give written informed consent.
- •Patients may have received previous radiation but must have completed radiation at least 2 weeks (8 weeks for radiation to the brain) prior to registration. Patients with irradiated tumor as the only site of evaluable disease will not be eligible for protocol therapy unless there is documented disease progression within the previously radiated site.
- •Patients must have recovered to grade </= 1 from all acute toxicity of previous radiation or hormonal therapy.
- •Adequate hematologic and hepatic function: Granulocyte count >/= 1,500/mcL, Platelet count >/= 100,000/mcL, Bilirubin </= 1.5 x ULN, AST and/or ALT </= 2 x ULN, Alkaline phosphatase (liver component, if fractionated) </= 2 x ULN, Serum Na, K+, Mg2+, Phosphate and Ca2+>/= Lower Limit of Normal (LLN) [subjects with low electrolyte levels must be repleted to normal for protocol entry]
- •Patients must not receive any concurrent bisphosphonate therapy other than that prescribed by the study.
- •Sexually active patients with reproductive potential must agree to use an effective method of birth control during the course of the study and for no less than 4 weeks after discontinuing study drug. Contraceptives must be used in a manner such that risk of failure is minimized. Oral contraceptives should be avoided in women with estrogen or progesterone receptor positive breast cancer.
- •Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control.
- •All WOCBP MUST have a negative serum or urine pregnancy test within 72 hours prior to the start of study drug administration. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study.
- •Patients with disease progression while receiving previous therapy in combination with bisphosphonates (including zoledronic acid) will be considered eligible for protocol participation.
排除标准
- •Any malignancy (other than breast cancer) that required radiotherapy or systemic treatment within the past 5 years.
- •Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade, clinically-significant coagulation or platelet function disorder (e.g. known von Willebrand's disease)
- •Cardiac Symptoms, including the following: Uncontrolled angina, congestive heart failure or MI within (6 months), diagnosed congenital long QT syndrome, any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), prolonged QTc interval on pre-entry electrocardiogram (> normal range), subjects with hypokalemia or hypomagnesemia if it cannot be corrected
- •History of significant bleeding disorder unrelated to cancer, including: diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies), ongoing or recent (</= 3 months) significant gastrointestinal bleeding
- •Concomitant Medications, consider the following prohibitions (Drugs must be discontinued for 7 days prior to starting protocol therapy):
- •Women and men of child bearing potential: who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study drug, or women of childbearing potential (CBP) who have a positive pregnancy test at baseline, or women who are pregnant or breastfeeding
- •Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
- •Untreated or uncontrolled brain metastasis
- •Patient inability to take or absorb oral medications
- •Current active dental problems including: ongoing infection of the teeth or jawbone (maxilla or mandibula); current exposed bone in the mouth; and current or prior diagnosis of osteonecrosis of the jaw
- •Recent (within 8 weeks) or planned dental or jaw surgery (e.g., extraction, implants)
- •Diagnosis of metabolic bone disease other than osteoporosis (e.g., Paget's disease of bone)
- •Known hypersensitivity to zoledronic acid or aspirin
- •Corrected serum calcium < 8.0 mg/dL (2.0 mmol/L) or >/= 12.0 mg/dL (3.0 mmol/L) at Visit
- •The formula to be used is: Corrected serum calcium (mg/dL) = Patient's serum calcium (mg/dL) + [0.8 x Midrange Albumin (g/dL) - Patient's Albumin (g/dL)]. 4.0g/dL to be used for the Midrange Albumin
- •Serum creatinine greater than or equal to 1.5 times the institutional upper limits of normal or a creatinine clearance of <40 ml/min when calculated by the Cockcroft and Gault formula (see protocol text for formula)
研究组 & 干预措施
Dasatinib + Zoledronic Acid
Dasatinib Phase I: First Cohort = 100 mg PO Daily x 28 days; Next Cohort = Dose Expansion or Reduction Based on Dose Limiting Toxicity (DLT) in Initial Cohort.
Zoledronic Acid Phase I: First Cohort = 4 mg IV Over 15 min. every 4 Weeks; Next Cohort = Dose Expansion or Reduction Based on Dose Limiting Toxicity (DLT) in Initial Cohort. Phase II: Recommended Phase II Dose (RP2D) as determined with Phase I.
干预措施: Dasatinib (Drug)
Dasatinib + Zoledronic Acid
Dasatinib Phase I: First Cohort = 100 mg PO Daily x 28 days; Next Cohort = Dose Expansion or Reduction Based on Dose Limiting Toxicity (DLT) in Initial Cohort.
Zoledronic Acid Phase I: First Cohort = 4 mg IV Over 15 min. every 4 Weeks; Next Cohort = Dose Expansion or Reduction Based on Dose Limiting Toxicity (DLT) in Initial Cohort. Phase II: Recommended Phase II Dose (RP2D) as determined with Phase I.
干预措施: Zoledronic Acid (Drug)
结局指标
主要结局
Objective Response in Bone From Time of Initiation of Therapy to > 6 Months
时间窗: 6 months
Objective response rate is defined as the clinical benefit rate (complete and partial response) + stable disease \> 6 months in bone.
Phase I - Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) for Dasatinib in Combination With Zoledronic Acid
时间窗: day 1 (+/- 48 hours) prior to therapy during cycle 2 and all subsequent cycles
To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for dasatinib in combination with zoledronic acid.
次要结局
未报告次要终点