A Phase II Study of Tazemetostat in Solid Tumors Harboring an ARID1A Mutation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Overall Response Rate
研究概览
简要总结
The FDA approved targeted agent tazemetostat inhibits EZH2 and induces durable tumor responses in patients with B-cell non-Hodgkin's lymphoma and epithelioid sarcomas. Responses have also been demonstrated in INI1 and SMARCA4 negative solid tumors patients. Since EZH2 plays a critical role in driving the biology of ARID1A mutated malignancies, we hypothesize that inhibition of EZH2 with tazemetostat will lead to significant clinical benefit in ARID1A mutated malignancies.
详细描述
AT rich interacting domain containing protein 1A (ARID1A) is a tumor suppressor gene frequently mutated in solid tumor malignancies, often loss of function mutations (frameshift or non-sense). ARID1A encodes a large nuclear protein BAF250a, a vital component of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, which participates in several nuclear activities including transcription, DNA synthesis and DNA damage repair. ARID1A alterations are particularly prevalent in ovarian clear cell carcinoma (46-50%), ovarian and uterine endometrioid carcinomas (24-44%), and cholangiocarcinoma (27%); reported in up to 27% of gastric carcinoma, esophageal adenocarcinoma, Waldenstrom macroglobulinemia, pediatric Burkitt lymphoma, hepatocellular carcinoma, urothelial carcinoma, 12% of colorectal carcinoma (CRC) , 15% of invasive ductal carcinoma of breast, and 7.5% of NSCLC, as a sample representation reported in the COSMIC database.
ARID1A plays a key role in regulating cell cycle and DNA damage repair, through its critical role in chromatin regulation. Loss of function of ARID1A leads to dysregulation of many gene pathways, supporting its role as a tumor suppressor gene. Loss of ARID1A mediates fulvestrant resistance, demonstrated in multiple elegant studies involving ER+ breast cancer lines, related to therapeutic pressure and selection [1]. Sporadic deletion of ARID1A in mice leads to de novo invasive colon adenocarcinoma. Loss of ARID1A leads to deregulation of the MEK/ERK pathway, critical in kras mutated CRC. ARID1A loss is associated with microsatellite instability in ovarian and endometrial endometrioid adenocarcinomas and gastric cancer. Preclinical data demonstrates enhanced clinical activity of check point inhibitors in ARID1A mutated tumors.
EZH2, enhancer of zeste homologue 2, the enzymatically active core of PRC2 (polycomb repression complex 2/3) plays a key role in tumorigenesis. Over-expression in tumor cells leads to histone hypermethylation, tumor proliferation, cell cycle dysregulation, metastases and angiogenesis.
Tazemetostat is an FDA approved selective small molecule inhibitor of the histone lysine methyltransferase enhancer of zeste homolog 2 (EZH2). Posttranslational modifications of core histone proteins of chromatin play an important role in controlling the fidelity of gene transcription patterns in cells. Paramount among these transcription-controlling modifications is methylation events at lysine and arginine residues, catalyzed by histone methyltransferases (HMTs). Genetic alterations in a number of HMTs have been identified in human cancers where they are purported to play a causal role in malignancies. Tazemetostat has been shown to produce durable tumor responses in patients with B-cell non-Hodgkin's lymphoma and epithelioid sarcomas. Responses have also been demonstrated in INI1 and SMARCA4 negative solid tumors patients.
Hypothesis: EZH2 plays a critical role in driving the biology of ARID1A mutated malignancies. Inhibition of EZH2 with tazemetostat will lead to significant clinical benefit in ARID1A mutated malignancies.
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
- •Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
- •Histologically and/or cytologically confirmed advanced or metastatic solid tumor harboring ARID1A mutation (except epithelioid sarcoma)
- •Progression of disease following approved therapies or for which no standard therapy exists
- •For subjects who have experienced any clinically significant toxicity related to a prior anticancer treatment (i.e., chemotherapy, immunotherapy, and/or radiotherapy): at the time the subject provides voluntary written informed consent, all toxicities have either resolved to grade 1 per NCI CTCAE Version 5.0 [11] OR are clinically stable and no longer clinically significant.
- •Have measurable disease as defined by RECIST 1.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •Males or females are >18 years of age at the time of providing voluntary written informed consent.
- •Life expectancy >3 months before enrollment.
- •Time between prior anticancer therapy and first dose of tazemetostat as follows:
- •Cytotoxic chemotherapy - At least 21 days Noncytotoxic chemotherapy (e.g., small molecule inhibitor) - At least 14 days. Nitrosoureas - At least 6 weeks. Monoclonal antibody - At least 28 days. Radiotherapy - At least 14 days. In addition, at least 6 weeks from prior radioisotope therapy; and at least 12 weeks from 50% pelvic or total body irradiation.
- •Adequate renal function: Creatinine < 2.0 or calculated creatinine clearance ≥ 35 mL/minute per the Cockcroft and Gault formula
- •Adequate bone marrow function:
- •ANC ≥ 750mm3 without growth factor support (filgrastim or pegfilgrastim) for at least 14 days.
- •Platelets ≥ 75,000mm3 (≥75 × 109/L) evaluated at least 7 days after platelet transfusion.
- •Hemoglobin ≥9.0 g/dL and may receive transfusion Adequate liver function: Total bilirubin <1.5 × the upper limit of normal (ULN) (except for unconjugated hyperbilirubinemia of Gilbert's syndrome); Alkaline phosphatase (ALP) (in the absence of bone disease), ALT, and AST <3 × ULN (or <5 × ULN if subject has liver metastases).
排除标准
- •Subjects with epithelioid sarcoma are excluded.
- •Has a prior history of T-Cell Lymphoblastic Lymphoma, T-Cell Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, Acute Myeloid Leukemia, or Myeloproliferative Neoplasm.
- •Female subjects who are pregnant or breastfeeding.
- •Prior exposure to tazemetostat or other inhibitor(s) of EZH
- •Subjects with uncontrolled CNS metastases requiring steroids.
- •Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
- •Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet.
- •Major surgery within 4 weeks before the first dose of study drug. NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 1 week prior to enrollment.
- •Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat.
- •Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II (Appendix 3), uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia.
- •Have an active infection requiring systemic therapy.
- •Known hypersensitivity to any component of tazemetostat.
- •Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the subject's participation in this study OR interfere with their ability to receive study treatment or complete the study.
- •Subjects who have undergone a solid organ transplant.
- •Prior malignancy in the past 5 years.
研究组 & 干预措施
Tazemetostat
tazemetostat 800 mg po twice daily in continuous 28- day cycles
干预措施: Tazemetostat (Drug)
结局指标
主要结局
Overall Response Rate
时间窗: through study completion, estimated to be 1 year after the last subject enrolled
Evidence of anti-tumor activity will be assessed by objective response, as defined by RECIST 1.1. This will be used to summarize ORR (CR+PR), as well as the rates for the individual categories of response, (i.e., CR, PR, SD, and PD).
次要结局
- Disease Control Rate(through study completion, estimated to be 1 year after the last subject enrolled)