A Phase I/II, Single Arm, Non-randomized Study of Ribociclib (LEE011), a CDK 4/6 Inhibitor, in Combination With Bicalutamide, an Androgen Receptor (AR) Inhibitor, in Advanced AR+ Triple-negative Breast Cancer: Big Ten Cancer Research Consortium BRE15-024
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 37
- 试验地点
- 6
- 主要终点
- Phase I: Maximum Tolerated Dose
研究概览
简要总结
This is an open label, multi-institutional, single arm phase II trial of ribociclib in combination with bicalutamide in advanced AR+ triple-negative breast cancer. No randomization or blinding is involved.
详细描述
This is a non-randomized, single arm, open label study of the combination of bicalutamide with ribociclib in subjects with advanced AR+ TNBC. Prior to enrollment on the phase II cohort, a phase I run-in study will be performed to ensure safety and tolerability of the combination of bicalutamide and ribociclib in subjects with advanced AR+ TNBC.
In both the phase I and phase II portions of the study, subjects will receive bicalutamide 150 mg orally, once daily, continuously on Day 1 to Day 28. Each cycle of treatment is 28 days.
In the phase I portion of the study, cohorts of subjects will receive ribociclib in escalated doses orally, once daily in a 28 day cycle. For the phase II portion, the RP2D dose of ribociclib will be based on the phase I run-in.
In the phase II cohort, a two week lead-in of bicalutamide monotherapy will occur before cycle 1 combination therapy (Day -14 to day -1). Then ribociclib will be added on day 1 of cycle 1. This lead-in will be for CTC androgen receptor analysis.
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
盲法说明
Open Label
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
- •Prior therapy with AR antagonists including but not limited to bicalutamide, enzalutamide, abiraterone and orteronel.
- •Prior therapy with any CDK 4/6 inhibitors with the exception of participation in a window or preoperative study for Stage I-III operable breast cancer..
- •Active infection requiring systemic therapy.
- •Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
- •Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three years.
- •Treatment with any investigational drug within 14 days prior to registration or within 5 half-lives of the investigational product, whichever is longer. Immunotherapies such as PD-L1 or PD-1 inhibitors only require a 14 day window, regardless of half-life. Investigational imaging agents are not included in this definition and are allowed.
- •Subject who has received radiotherapy <14 days prior to registration, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia and any adverse events deemed by the investigator to be unlikely to interfere with the study drug safety).
- •Subject has had major surgery within 14 days prior to registration or has not recovered from major side effects of the surgery (tumor biopsy is not considered as major surgery).
- •Known hypersensitivity to any of the excipients of ribociclib or bicalutamide.
- •Any impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
- •Known history of HIV infection (testing not mandatory).
- •Any concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate subject participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.).
- •Subjects with any of the following conditions are excluded:
- •Serious or non-healing wound, ulcer, or bone fracture.
- •History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 28 days prior to registration.
- •Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to registration.
- •Any history of arterial or venous thrombosis/thromboembolic event, including pulmonary embolism within the past 12 months prior to registration.
- •History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to registration.
- •Symptomatic congestive heart failure (New York Heart Association III-IV) or documented current cardiomyopathy with left ventricular ejection fraction (LVEF) <50%
- •Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia) or clinically significant, complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block).
- •Any episode of atrial fibrillation in the prior 12 months.
- •Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
- •Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication. See ManualDocuments/Info tab of the EDC for list of medications.
- •Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening.
- •Currently receiving any known strong inducers or inhibitors of CYP3A4/5 which cannot be discontinued 7 days prior to starting study drug (see Appendix 1 for details).
- •Subject is currently receiving or has received systemic corticosteroids <14 days prior to starting study drugs. The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroidssingle doses, any duration of topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
- •Subject is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), novel oral anticoagulants (NOACs) or fondaparinux is allowed.
- •In subjects with a diagnosis of cirrhosis, sSubjects with a Child-Pugh score B or C are excluded. Please see chart in the ManualDocuments/Info tab of the electronic data capture system (EDC) for Child-Pugh score calculation. If subject does not have diagnosed or suspected cirrhosis, the Child-Pugh score does not need to be calculated.
- •Subjects taking herbal supplements (St. John's Wort, gingko balboa, etc.) must discontinue these supplements 14 days prior to study registration.
- •Consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, Seville oranges or products containing the juice of each within 7 days prior to study registration.
研究组 & 干预措施
Arm A - Phase I
Dose Escalation Cohort 1 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-21 of a 28 day cycle.
Cohort 2 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-28 of a 28 day cycle.
Cohort 3 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 600mg PO daily on days 1-21 of a 28 day cycle.
Experimental: Arm B - Phase II Investigational Treatment The maximum safe dose of ribociclib in combination with bicalutamide will be given to up to 25 patients.
干预措施: ribociclib (Drug)
Arm A - Phase I
Dose Escalation Cohort 1 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-21 of a 28 day cycle.
Cohort 2 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-28 of a 28 day cycle.
Cohort 3 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 600mg PO daily on days 1-21 of a 28 day cycle.
Experimental: Arm B - Phase II Investigational Treatment The maximum safe dose of ribociclib in combination with bicalutamide will be given to up to 25 patients.
干预措施: Bicalutamide (Drug)
结局指标
主要结局
Phase I: Maximum Tolerated Dose
时间窗: D1 of treatment to end of cohort cycle (assessed at 28 days)
Phase I: Maximum tolerated dose (MTD) for subjects receiving ribociclib and bicalutamide without experiencing dose-limiting toxicity(s) (DLT) per Common Terminology Criteria for Adverse Events (CTCAE) v4
Phase II: Clinical benefit rate (CBR) of treatment combination
时间窗: D1 of treatment to end of 4 treatment cycles (assessed at 16 weeks)
Compare sum of confirmed complete plus partial responses plus stable disease per response evaluation criteria in solid tumors (RECIST) 1.1 criteria
次要结局
- Phase I: Ribociclib pharmacokinetics(2 months)
- Phase II: Objective Response Rate (ORR)(2 years)
- Phase II: Estimate Duration of Response(2 years)
- Phase I: Objective Response Rate (ORR)(2 years)
- Phase II: Progression Free Survival (PFS)(2 years)
- Phase II: Overall Survival (OS)(5 years)
- Phase II: Evaluate Safety and Tolerability By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)(2 years)
- Phase I: Duration of Response(2 years)
- Phase I: Assess Safety and Tolerability By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)(2 years)
研究者
Kari Wisinski
Sponsor Investigator
Big Ten Cancer Research Consortium