A Phase I Study With Expansion Cohort of Concurrent GDC-0084 With Radiation Therapy for Patients With Solid Tumor Brain Metastases or Leptomeningeal Metastases Harboring PI3K Pathway Mutations
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 21
- 试验地点
- 17
- 主要终点
- maximum tolerated dose (MTD)
研究概览
简要总结
This study will test the safety of the study drug, GDC-0084, in combination with radiation therapy in people who have solid tumor brain metastases or leptomeningeal metastases. All participants will have cancer with a PIK3CA mutation. The researchers will test increasing doses of GDC-0084 to find the highest dose that causes few or mild side effects in participants. The study will also try to find out if the combination of the study drug with radiation is effective against participants' cancer.
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
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed solid tumor malignancies harboring PIK3CA mutations which include mutations in any of the following genes: PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3C2G, PIK3C3, INPP4A, INPP4B, INPPL1, INPP5D, PTEN, AKT1, AKT2, AKT3, and MTOR.
- •Brain metastases and/or leptomeningeal metastases involving the brain demonstrated by MR imaging of the brain. For patients with brain metastases, measurable lesion by RANO-BM is required
- •Patients with spine leptomeningeal metastases are eligible for the study if they have leptomeningeal metastases of the brain demonstrated by MRI imaging of the brain.
- •Age ≥ 18 years
- •Able to provide informed consent.
- •If a patient is on corticosteroid, he/she must be on a stable daily dose of < 4mg dexamethasone or equivalent. Patient does not need to be given corticosteroid as prophylaxis if not clinically indicated.
- •No limit to prior therapies with the last systemic therapy ≥ 1 week from initiation of protocol therapy. Systemic therapy can resume after completion of protocol DLT assessment period.
- •Patients with prior SRS are eligible, provided that there are new, non-irradiated brain lesions or leptomeningeal metastases. Patients must be ≥ 3 months post prior cranial radiation therapy.
- •Patients with seizure history related to brain metastases or leptomeningeal metastases controlled on antiepileptic medications are eligible.
- •Patient at reproductive potential must agree to practice an effective contraceptive method
- •Patient must be able to swallow and retain oral medication
- •Adequate organ function as assessed by laboratory tests.
- •Adequate bone marrow function
- •Hemoglobin ≥ 8g/dL
- •Absolute neutrophil count ≥1,000/mm^3
- •Platelet count ≥ 100,000/mm^3
- •Adequate liver function
- •Bilirubin ≤1.5 times upper limit normal (ULN)
- •AST and ALT ≤ 2.5 times ULN
- •Alkaline phosphatase ≤ 2 times ULN
- •Adequate renal function ° BUN and Creatinine ≤ 1.5 times ULN
排除标准
- •Previous radiotherapy to the intended treatment site that precludes developing a treatment plan that respects tissue tolerances
- •Patients with brain metastases eligible for single fraction stereotactic radiation therapy
- •Serious medical co-morbidities precluding radiotherapy
- •Insulin-treated diabetes; subjects with diabetes or impaired glucose tolerance that is not treated with insulin may be enrolled
- •QT interval ≥ 450 msec on EKG
- •Cardiac dysfunction defined as: myocardial infarction within 6 months of study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac arrhythmias
- •Known hypersensitivity or intolerance to GDC-0084 or to any other inhibitor of the PI3K/ Akt/ mTOR pathway
- •Past medical history of interstitial lung disease, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease
- •Subject receiving any medications or substances that are moderate and/or potent enzyme inducers or inhibitors which may have an effect on the metabolism of GDC-
- •Pregnant or lactating women.
研究组 & 干预措施
Concurrent GDC-0084 with Radiation
GDC-0084 in 3 + 3 dose-escalation in 3 cohorts: 45, 60, 75 mg daily, with a potential de-escalation cohort to 30mg, to determine MTD in combination with whole brain radiation therapy radiation therapy to 30Gy in 10 fractions. Once MTD is determined, 12 additional patients will be treated with GDC-0084 at MTD in combination with whole brain radiation therapy.
干预措施: GDC-0084 (Drug)
Concurrent GDC-0084 with Radiation
GDC-0084 in 3 + 3 dose-escalation in 3 cohorts: 45, 60, 75 mg daily, with a potential de-escalation cohort to 30mg, to determine MTD in combination with whole brain radiation therapy radiation therapy to 30Gy in 10 fractions. Once MTD is determined, 12 additional patients will be treated with GDC-0084 at MTD in combination with whole brain radiation therapy.
干预措施: whole brain radiation therapy radiation (Radiation)
结局指标
主要结局
maximum tolerated dose (MTD)
时间窗: 1 year
Four dose levels will be examined and the maximum tolerated dose (MTD) will be identified. The standard 3+3 dose-escalation scheme for this study is as follows. Patients will be accrued to the study in cohorts of 3. For any given dose an initial cohort of 3 patients will be treated at that dose.The dose level will be escalated if none of the 3 exhibits any dose limiting toxicity (DLT).
次要结局
- local recurrence rate(1 year)