NCT01300962已完成1 期
A Four Part, Phase I Dose-Escalation Study of the Combinations of Concurrent BKM120 and Capecitabine, or Concurrent BYL719 and Capecitabine, or Concurrent BKM120 and Capecitabine and Trastuzumab, or Concurrent BKM120 and Capecitabine and Lapatinib in Patients With Metastatic Breast Cancer
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 2
- 主要终点
- Dose limiting toxicity (DLT)
研究概览
简要总结
This phase I study has been designed to establish the safety, tolerability and maximum tolerated dose (MTD) of four separate regimens for patients with metastatic breast cancer: dose- escalating BKM120 when combined with capecitabine (Arm A), with capecitabine and trastuzumab (Arm C), or with capecitabine and lapatinib (Arm D) and dose- escalating BEZ235 when combined with capecitabine (Arm B).
详细描述
STUDY OBJECTIVES Primary Objectives
- To determine the safety, DLT, and MTD of BKM120 when administered concomitantly with capecitabine in patients with metastatic breast cancer (ARM A)
- To determine the safety, DLT, and MTD of BYL719 when administered concomitantly with capecitabine in patients with metastatic breast cancer (ARM B)
- To determine the safety, DLT, and MTD of BKM120 when administered concomitantly with capecitabine and trastuzumab in patients with metastatic breast cancer (ARM C)
- To determine the safety, DLT, and MTD of BKM120 when administered concomitantly with capecitabine and lapatinib in patients with metastatic breast cancer (ARM D)
Secondary Objectives
- To characterize the safety and tolerability of BKM120 in combination with capecitabine including acute and chronic toxicities
- To characterize the safety and tolerability ofBYL719 in combination with capecitabine including acute and chronic toxicities
- To characterize the safety and tolerability of BKM120 in combination with capecitabine and trastuzumab, including acute and chronic toxicities
- To characterize the safety and tolerability of BKM120 in combination with capecitabine and lapatinib, including acute and chronic toxicities
Exploratory Objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- 未提供
排除标准
- •Subjects meeting any of the exclusion criteria listed below at baseline will be excluded from study participation:
- •Receiving concurrent endocrine, cytotoxic, or biologic agent(s) or within time limits specified above prior to study day 1
- •Receiving any other investigational agents currently, or within time limits specified above prior to study day 1
- •Received wide field radiotherapy ≤4 weeks, or SRS or gamma knife for brain metastasis ≤ 2 weeks or limited field radiation for palliation ≤2 weeks prior to starting either BYL719 or BKM120 or have not recovered from side effects of such therapy
- •Have undergone major surgery ≤2 weeks prior to starting BKM120 or BYL719 or have not recovered from side effects of such therapy
- •Prior treatment with treatment doses of capecitabine (prior radio-sensitizing doses of capecitabine are allowed as long as the patient did not progress on capecitabine)
- •Prior treatment with a PI3K inhibitor
- •Known dihydropyrimidine dehydrogenase (DPD) deficiency
- •Treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
- •Currently receiving treatment with medication known to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug
- •Patients currently receiving chronic systemic treatment with steroids or another immunosuppressive agent; NOTE: This restriction regarding choice of glucocorticoid does not apply should patient need <2 week course of glucocorticoid for treatment of non-infectious pneumonitis during study, or if ARM C patient with brain metastases treated with glucocorticoid is enrolled. Topical applications (e.g., rash), inhaled sprays, eye drops or local injections of steroids are allowed.
- •Known coagulopathies, and those who require therapeutic anticoagulation with coumarin-derivative anticoagulants
- •Presence of acute or chronic liver, renal disease, or pancreatitis
- •For all Arms, patients with poorly controlled diabetes mellitus, and/or with clinical signs, and/or steroid-induced diabetes mellitus; for Arm B, patients requiring insulin treatment
- •History of gestational diabetes mellitus
- •Known diagnosis of human immunodeficiency virus (HIV) infection
- •For Arms A, C or D, patients with the following mood disorders as judged by the investigator or a psychiatrist, or as result of patient's mood assessment questionnaire:
- •Medically documented history of major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) or patients with active severe personality disorders (defined according to DSM-IV). NOTE: for patients with psychotropic treatments ongoing at baseline, the dose and schedule should not be modified within the previous 6 weeks prior to D1 of treatment with BKM120
- •≥ CTCAE grade 3 anxiety
- •At screening, meets the cut-off score of ≥10 in the Patient Health Questionnaire (PHQ-9) or a cut-off of ≥ 15 in the Generalized Anxiety Disorder (GAD-7) mood scale, respectively, or selects a positive response of 1, 2 or 3 to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) will be excluded from the study unless overruled by the psychiatric assessment
- •Note: The psychiatric judgment overrules the mood assessment questionnaire result/investigator's judgment.
- •Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study medication and during the entire study due to potential CYP3A4 interaction with the study medication. Orange juice is allowed
- •Intake of any herbal preparations or medications (e.g., including, but not limited to, Saint-Johns Wort and ginkgo biloba) and dietary supplements within 7 days prior to first dose of study drug
- •For ARMS A, C and D, unable or unwilling to discontinue use of any drug known to be a strong or moderate inhibitor or inducer of CYP3A4 (prohibited inducers and inhibitors must be discontinued within 2 weeks prior to first dose of study drug) (see Appendix B); please note that co-treatment with weak inhibitors of CYP3A4 is allowed.
- •Patients who received live vaccines or who have close contact with people who have received live vaccines within 7 days of day 1 of study treatment (see Appendix B)
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 or BYL719 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); Patients with unresolved diarrhea will be excluded.
- •Inadequately controlled hypertension (i.e. SBP >180 mmHg or DBP >100mmHg)
- •Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
- •Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO)
- •ST depression or elevation of ≥1.5 mm in 2 or more leads
- •Congenital long QT syndrome
- •History or presence of ventricular arrhythmias or atrial fibrillation
- •Clinically significant resting bradycardia (<50 beats per minutes)
- •QTc >480 msec on screening ECG
- •Complete left bundle branch block
- •Right bundle branch block + left anterior hemiblock (bifascicular block)
- •Unstable angina pectoris ≤6 months prior to starting study drug
- •Acute myocardial infarction ≤6 months prior to starting study drug
- •Other clinically significant heart disease such as congestive heart failure requiring treatment (New York Heart Association [NYHA] Class III or IV)
- •Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
- •Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, 02 saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates
- •Prior malignancy Exceptions: Subjects who have had another malignancy and have been disease-free for 3 years or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition of BKM120, BYL719, capecitabine (including fluorouracil), trastuzumab or lapatinib
- •Pregnant or lactating women
- •Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator
研究组 & 干预措施
BYL719 ARM B
Experimental
Treatment with BYL719 and Capecitabine
干预措施: Capecitabine (Drug)
BYL719 ARM B
Experimental
Treatment with BYL719 and Capecitabine
干预措施: BYL719 (Drug)
BKM120 ARM A
Experimental
Treatment with BKM120 and capecitabine
干预措施: BMK120 (Drug)
BKM120 ARM A
Experimental
Treatment with BKM120 and capecitabine
干预措施: Capecitabine (Drug)
ARM C
Experimental
BKM 120 plus capecitabine plus trastuzumab
干预措施: BMK120 (Drug)
ARM C
Experimental
BKM 120 plus capecitabine plus trastuzumab
干预措施: Capecitabine (Drug)
ARM C
Experimental
BKM 120 plus capecitabine plus trastuzumab
干预措施: Trastuzumab (Drug)
ARM D
Experimental
BKM120 plus capecitabine plus lapatinib
干预措施: BMK120 (Drug)
ARM D
Experimental
BKM120 plus capecitabine plus lapatinib
干预措施: Capecitabine (Drug)
ARM D
Experimental
BKM120 plus capecitabine plus lapatinib
干预措施: Lapatinib (Drug)
结局指标
主要结局
Dose limiting toxicity (DLT)
时间窗: two years
Dose-limiting toxicities (DLT) will be defined per NCI Common Terminology Criteria for Adverse Events version 4 (CTCAE v4)
Maximum Tolerated Dose
时间窗: two years
Maximum Tolerated Dose (MTD) will be the highest does at which less than or equal to 1 out of 6 patients have experienced a dose limiting toxicity (DLT)
次要结局
- Objective Response(two years)
- Best Overall Response(two years)
研究者
研究点 (2)
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