Phase I/II Study of T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Phase I: Maximum Tolerated Dose (MTD) of Temozolomide (TMZ) When Used With T-DM1 (Ado-trastuzumab)
研究概览
简要总结
Background:
Sometimes breast cancer spreads (metastasizes) to the brain. Researchers want to study new treatments for brain metastases. The drug Temozolomide is approved to treat brain tumors. Researchers want to see if combining it with the drug trastuzumab emtansine (T-DMI) prevents the formation of new metastases in the brain.
Objective:
To study if Temozolomide with T-DM1 lowers the chance of having new metastases in the brain.
Eligibility:
Adults at least 18 years old with a human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to the brain and was recently treated with stereotactic radiation or surgery.
Design:
Participants will be screened with
- Medical history
- Physical exam
- Heart tests
- A scan (computed tomography (CT) that makes a picture of the body using a small amount of radiation
- A scan (magnetic resonance imaging (MRI) that uses a magnetic field to make an image of the brain
- Blood tests.
- Pregnancy test.
The study will be done in 3-week cycles.
All participants will get T-DM1 on Day 1 of every cycle through a small plastic tube inserted in an arm vein.
Some participants will also take Temozolomide capsules by mouth every day.
Participants will keep a medication diary.
During the study, participants will also:
- Repeat most of the screening tests.
- Answer questions about their general well-being and functioning.
Participants will have lumbar puncture at least 2 times. A needle is inserted into the spinal canal low in the back and cerebrospinal fluid is collected. This will be done with local anesthesia and with the help of images.
Participants will be asked to provide tumor samples when available.
Participants will have a follow-up visit about 1 month after stopping the study drug. They will be contacted by telephone or email every 3 months after that.
详细描述
Background:
- Breast cancer is the most common cancer in women. In the human epidermal growth factor receptor 2 (HER2+) subtype, brain metastases can occur in up to 25-40% of patients.
- The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).
- Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients.
- Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion.
- Our group has shown in vitro and in vivo in animal models injected with a brain tropic O6-methylguanine DNA methyltransferase (MGMT) + cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases.
- We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease.
Objectives:
- Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1.
- Phase II: to determine if the combination regimen of trastuzumab emtansine (T-DM1) and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation
T-DM1 + TMZ in dose escalation
干预措施: T-DM1 (Drug)
1/Phase I: Ado-trastuzumab (T-DMI) + Temozolomide (TMZ) Dose Escalation
T-DM1 + TMZ in dose escalation
干预措施: TMZ (Drug)
2A /Phase II: Arm A, Ado-trastuzumab (T-DMI) Alone
T-DM1
干预措施: T-DM1 (Drug)
2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)
T-DM1 + TMZ at recommended phase 2 dose (RP2D)
干预措施: T-DM1 (Drug)
2B/Phase II /Arm B, Ado-trastuzumab (T-DMI) + Temozolomide (TMZ)
T-DM1 + TMZ at recommended phase 2 dose (RP2D)
干预措施: TMZ (Drug)
结局指标
主要结局
Phase I: Maximum Tolerated Dose (MTD) of Temozolomide (TMZ) When Used With T-DM1 (Ado-trastuzumab)
时间窗: first 21 days of treatment
Maximum tolerated dose of TMZ when used in combination with T-DM1. MTD is defined as the dose level at which 0 or 1 participant in 6 has a dose limiting toxicity (DLT). A DLT is defined as grade 3 or higher non-hematologic adverse events excluding grade 3 hypertension controlled with anti-hypertensive therapy; or grade 3 asymptomatic electrolytes imbalance; grade 3 endocrinopathy; grade 3 asymptomatic increase in aspartate aminotransferase or alanine aminotransferase; and transient (lasting less than \<48 hours) nausea, emesis, or diarrhea if corrected with conservative measures within 24-48 hours. A hematologic grade 4 neutropenia of ≥ 7 days duration, grade ≥ 3 thrombocytopenia, and all other grade 4 hematologic toxicities excluding grade 4 lymphopenia, or leukopenia in the absence of grade 3 or higher neutropenia. Grade 3 is severe. Grade 4 is life-threatening.
Phase II: Median Amount of Time Participant Survives Without New Brain Lesions After Starting Treatment
时间窗: From the start of treatment until new brain lesions
Median time to progression. Progression was assessed using the Response Assessment in Neuro-oncology Brain Metastases (RANO-BM) Criteria for evaluation of brain lesions, and the Response Evaluation Criteria in Solid Tumors (RECIST) for systemic evaluation. Progression is a 25% increase in the sum of products of all measurable lesions observed over baseline if no decrease. Or appearance of new lesions, or failure to return for evaluation due to death or deteriorating condition.
次要结局
- Phase I: Number of Participants With Dose Limiting Toxicity (DLTs) at Each Dose Level(After first cycle of treatment, up to 30 days)
- Phase I: Median Survival(From date of first therapy until death, an average of 40.79 months)
- Phase I: Number of Participants With Grade 3 and/or Grade 4 Adverse Events(Evaluated at the beginning of every cycle while on study, for an average of 9.6 months (range 2.8-33.9 months).)
- Phase II: Time to Whole Brain Irradiation(At progression)
- Phase II: Median Survival(At death)
- Phase I: Standard Time to Progression (TTP)(From first day of treatment to the day of disease progression, an average of 15 months.)
研究者
Stanley Lipkowitz, MD, PhD
Principal Investigator
National Cancer Institute (NCI)