NCT01791478已完成1 期
A Phase Ib Trial of BYL719 (an α-Specific PI3K Inhibitor) in Combination With Endocrine Therapy in Post-Menopausal Patients With Hormone Receptor-Positive Metastatic Breast Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 4
- 主要终点
- Maximum tolerated dose of BYL719 in combination with letrozole
研究概览
简要总结
This phase I trial studies the side effects and best dose of the PI3K inhibitor BYL719 when given together with letrozole in treating patients with hormone receptor-positive metastatic breast cancer. The PI3K inhibitor BYL719 may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving the PI3K inhibitor BYL719 together with letrozole may kill more tumor cells
详细描述
PRIMARY OBJECTIVE: To determine the safety and tolerability of BYL719 given in combination with endocrine therapy in post-menopausal patients with hormone receptor-positive metastatic breast cancer by determining:
I. Dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1).
II. Maximum tolerated dose (MTD) of BYL719 (PI3K inhibitor BYL719) given in combination with letrozole.
III. Highest tolerated dose - ability to tolerate BYL719 with letrozole for a total of 8 weeks without development of:
- Hyperglycemia (fasting glucose > 200 mg/dL) for more than 2 weeks in a row despite optimal medical treatment
- CTC Grade 3 or > rash for more than 2 weeks in a row despite optimal medical treatment
- CTC Grade 2 or > GI toxicity for more than 2 weeks in a row despite optimal medical treatment
- CTC Grade 2 or > serum creatinine, bilirubin, AST, ALT elevation from baseline for more than 2 weeks in a row despite optimal medical treatment
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Patients must provide informed written consent.
- •Patients must be >/= 18 years of age.
- •ECOG performance status 0 -
- •Clinical stage IV invasive mammary carcinoma, ER-positive and/or PR-positive by immunohistochemistry (IHC) and HER2 negative (by IHC or ISH). Patients may have either measurable or non-measurable disease, both are allowed.
- •A minimum of 10 patients in the trial (~50%) will need to have a PIK3CA mutation in their cancer
- •Patients must have had at least one line of endocrine therapy in the metastatic setting, or be diagnosed with metastatic breast cancer during or within 1 year of adjuvant endocrine therapy. There is no limit on lines of prior treatment in the metastatic setting.
- •Patients must have available tissue (archived formalin-fixed paraffin embedded blocks (FFPB) or fresh frozen tissue from original diagnosis or metastatic setting) for correlative studies. Tissue needs to be located and available at the time of registration (tissue needs to be submitted within 3 weeks of study initiation). Patients will not be able to start study drugs without tissue availability.
- •Life expectancy ≥ 6 months
- •Patients must have adequate hematologic, hepatic, and renal function. All laboratory tests must be obtained less than 1 week from study entry. This includes:
- •ANC >/= 1,500/mm3
- •platelet count >/=100,000/mm3
- •HgB ≥ 9 g/dL
- •Creatinine ≤ 1.5x ULN
- •Fasting plasma glucose ≤ 140 mg/dL
- •HgBA1C ≤ 8%
- •Total Serum Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
- •SGOT, SGPT ≤ 3 X ULN if no liver metastasis present
- •SGOT, SGPT ≤ 5 X ULN if liver metastasis present
- •Patients must be able to swallow and retain oral medication.
- •Patients must be post-menopausal. Post-menopausal female subjects should be defined prior to protocol enrollment by any of the following:
- •Subjects at least 55 years of age; OR
- •Subjects under 55 years of age and naturally (spontaneous) amenorrhea for at least 12 months or follicle-stimulating hormone (FSH) values ≥ 40 IU/L and estradiol levels </= 20 IU/L; OR
- •Prior bilateral oophorectomy; OR
- •Prior radiation castration with amenorrhea for at least 6 months
- •NOTE: Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (such as goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
- •Patients must complete all screening assessments as outlined in the protocol.
排除标准
- •* Locally recurrent resectable breast cancer.
- •* Any kind of malabsorption syndrome significantly affecting gastrointestinal function.
- •* Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or with fasting glucose \>/= 140 mg/dL / 7.8 mmol/L), history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus.
- •* Patients who have received radiation therapy \ grade 1, except for alopecia.
- •* Prior therapy with a PI3K inhibitor. Prior use of Akt or mTOR inhibitors are allowed.
- •* Patients who have received herbal medications \ grade 2, lung conditions requiring oxygen therapy)
- •3. symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)
- •4. Left Ventricular Ejection Fraction (LVEF) \< 50%
- •5. unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
- •6. uncontrolled hypertension within 2 weeks of study initiation (systolic blood pressure \> 180 mm Hg or diastolic blood pressure \> 110 mm Hg, found on two consecutive measurements separated by a 1 or 2-week period despite adequate medical support)
- •7. clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy,trigeminy, ventricular tachycardia that is symptomatic or requires treatment \[National Cancer Institute -Common Terminology Criteria for Adverse Events, Version 4.0, grade 3\]
- •8. QTcF ≥ 480 msec on screening EKG
- •9. known history of QT/QTc prolongation or Torsades de Pointes (TdP)
- •10. ST depression or elevation of ≥ 1.5 mm in 2 or more leads
- •11. Diarrhea of any cause ≥ CTCAE grade 2
- •12. psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary
- •13. patients with symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment)
- •14. patients with known history of chronic liver or renal failure
- •15. patients with known history of chronic or acute pancreatitis
- •Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age or race in the clinical trial outlined. This trial is open to the accrual of women.
研究组 & 干预措施
Treatment (PI3K inhibitor BYL719, letrozole)
Experimental
Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: PI3K inhibitor BYL719 (Drug)
Treatment (PI3K inhibitor BYL719, letrozole)
Experimental
Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Treatment (PI3K inhibitor BYL719, letrozole)
Experimental
Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological studies (Other)
Treatment (PI3K inhibitor BYL719, letrozole)
Experimental
Patients receive PI3K inhibitor BYL719 PO QD and letrozole PO QD. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: letrozole (Drug)
结局指标
主要结局
Maximum tolerated dose of BYL719 in combination with letrozole
时间窗: 4 weeks
Highest dose of BYL719 tested in which a DLT is experienced by 0 out of 3 or 1 of 6 patients, based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
次要结局
- Highest tolerated dose of BYL719 in combination with letrozole(8 weeks)
- Clinical benefit rate(At 6 months of study treatment)
- Overall progression-free survival(Up to 4 weeks after interruption of study treatment)
- Overall response(Every 8 weeks to interruption of treatment)
- Worst grade toxicities(Up to 4 weeks after interruption of study treatment)
研究者
Laura Kennedy
Assistant Professor of Medicine
Vanderbilt-Ingram Cancer Center
研究点 (4)
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