Window of Opportunity Analysis of Pre-Operative Tucatinib for Surgically Resected HER2+ Brain Metastases: Understanding Mechanisms of Resistance
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 28
- 试验地点
- 7
- 主要终点
- Maximum observed plasma concentration (Cmax) of Tucatinib
研究概览
简要总结
The purpose of this study to see how the brain absorbs, distributes, and gets rid of tucatinib in people who have HER2+ cancers (breast cancer, NSCLC, CRC, or GEC) that have spread to the brain, and to learn more about how cancer cells develop resistance to treatment. The researchers will do research tests to look for genetic differences between HER2+ breast cancer that has spread to the brain and progressed during treatment with tucatinib and cancers that are being treated with tucatinib for the first time.
详细描述
All patients will receive tucatinib per-protocol at standard dose of 300 mg orally twice daily on days - 4, -3, -2, -1 and day 0 (in AM). The post-surgery treatment (systemic and/or local) will be decided according to treating physician discretion and is not a study intervention. Tissue samples of brain metastases along with blood/plasma and CSF samples will be analyzed to evaluate brain tumor penetration of tucatinib as well as biologic response to tucatinib in patients with brain metastases from HER2+/mutant breast cancer who are undergoing clinically indicated brain surgery. Patients may continue tucatinib post-operatively at the discretion of the treating oncologist with monitoring as per clinical routine; this is not a study intervention for Cohort A and Cohort B. Patients on Cohort C may receive tucatinib post-operatively through the study according to physician descretion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Age ≥18 years with no impairment in decision making capacity
- •Patients with HER2 overexpressed/amplified/mutant metastatic breast/lung/esophagogastric/colorectal cancer (IHC, fluorescent in situ hybridation or sequencing-confirmed primary, brain, or other metastatic site) and one or more brain tumor(s) planned for neurosurgical resection. Other untreated brain metastases, and prior radiation (whole brain radiation therapy and/or stereotactic radiosurgery) to the index site are allowed
- •Patients with concomitant leptomeningeal disease are eligible provided they have parenchymal brain metastases requiring resection.
- •Life expectancy of >12 weeks.
- •ECOG Performance Status (PS) of 0 to 2
- •Prior treatments:
- •Cohort A: Clinical and or radiological CNS parenchymal progression on tucatinib as most recent line of treatment (tucatinib-resistant) in patients with HER2 overexpressed/amplified breast cancer
- •Clinical and or radiological CNS parenchymal progression with no prior tucatinib (tucatinib naïve) in patients with HER2 overexpressed/amplified breast cancer
- •Clinical and or radiological CNS parenchymal progression in patients with HER2+/mutant lung/esophagogastric/colorectal cancer and HER2 mutant breast cancer
- •ALL PATIENTS:
- •Prior conventional dose lapatinib and neratinib are allowed in any cohort if > 6 months prior
- •No limit on prior lines of systemic therapy
- •Adequate bone marrow, liver, renal function, and coagulation parameters (obtained ≤ 7 days prior to the first day of study treatment:
- •Absolute neutrophil count (ANC) ≥1.0 × 103μL, Platelet count ≥75 × 103 /μL, Hemoglobin ≥ 8.0 g/dL
- •Total bilirubin ≤1.5 × upper limit of normal (ULN). Subjects with known history of Gilbert's Syndrome and normal direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are eligible: AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastases are present)
- •Calculated creatinine clearance ≥50 mL/min using the CKD-EPI (2021) (in Cohort A, in patients with elevated serum creatinine, eGFR can be calculated using cystatin C to confirm eligibility)
- •International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless on medication known to alter INR and/or aPTT
- •Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to enrollment and must agree to use adequate contraception prior to enrollment and for the duration of study participation
- •Patients must be able to swallow and retain oral medication
排除标准
- •Contraindications or history of allergic reaction to tucatinib or any of its excipients
- •Significant medical co-morbidities as per investigator evaluation
- •Inability to comply with protocol and /or not willing or not available for follow-up assessments or any condition which in the investigator's opinion makes the patient unsuitable for the study participation
- •Have used a strong or moderate CYP2C8 inhibitor within 5 half-lives of the inhibitor or have used a strong or moderate CYP2C8 or CYP3A4 inducer within 2 weeks prior to first dose of study treatment (Appendix E)
- •Receiving concomitant CYP3A or P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities
- •Concurrent pregnancy
研究组 & 干预措施
Patients with documented radiological and/or clinical CNS progression with no prior tucatinib
Cohort B: Is to administer Tucatinib at standard dose of 300mg orally twice daily for 4 days prior to surgery (day -4 to 0).
干预措施: Tucatinib (Drug)
Patients already on Tucatinib
Cohort A: This is a non-interventional study patients who will enter while already on Tucatinib . Patients in cohort A who are already on Tucatinib at a dose reduction (i.e., for toxicity) will continue the same dose.
干预措施: Tucatinib (Drug)
HER2+ esophagogastric, lung, or colon cancer brain metastases and HER2 mutant breast cancer
Cohort C: Is to administer Tucatinib at standard dose of 300mg orally twice daily for 4 days prior to surgery (day -4 to 0).
干预措施: Tucatinib (Drug)
结局指标
主要结局
Maximum observed plasma concentration (Cmax) of Tucatinib
时间窗: 3 days after treatment
by measurement of intrametastasis levels
次要结局
未报告次要终点