NCT05960773招募中2 期
Phase II Evaluation of Decitabine/Cedazuridine (INQOVI), an Oral DNA Demethylating Agent in Subjects With BAP1 Cancer Predisposition Syndrome and Subclinical, Early-Stage Mesothelioma
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 15
- 试验地点
- 2
- 主要终点
- To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment
研究概览
简要总结
This is a Phase II study to determine the rate of stabilization or disease improvement from investigational decitabine/cedazuridine (INQOVI) treatment in subjects with BRCA1-Associated Protein-1 (BAP1) Cancer Predisposition Syndrome (CPDS) and subclinical, early-stage mesothelioma. Progression-free survival (PFS) will also be determined for treated subjects, and the treatment safety (toxicity) evaluated....
详细描述
Background:
- Mutations involving BRCA1-Associated Protein-1 (BAP1), a nuclear deubiquitinase involved in epigenetic regulation of gene expression, DNA repair, and cellular energetics, have emerged as one of the most common somatic mutations in malignant mesotheliomas.
- Germline mutations involving BAP1 predispose individuals to mesotheliomas and a variety of other malignancies including melanomas, as well as lung, renal, gastric, breast, and hepatobiliary carcinomas.
- The cancer penetrance of germline BAP1 mutations is nearly 100%, and most patients develop multiple synchronous or metachronous neoplasms.
- Mesotheliomas are the most common malignancies diagnosed in subjects with BAP1 Cancer Predisposition Syndrome (CPDS).
- Although clinically evident mesotheliomas arising in the context of germline BAP1 mutations tend to be more indolent than more common, sporadic mesotheliomas, the natural history of early-stage mesotheliomas in subjects with BAP1 CPDS is unknown.
- Presently there are no established guidelines for the treatment of subclinical malignancies in subjects with BAP1 CPDS.
- Epigenetic aberrations including those related to the up regulation of DNA methyltransferases (DNMT) induce genomic instability and enhance the growth and invasion of mesothelioma cells.
- Over-expression of DNMT1 also promotes the development of an immunosuppressive tumor micro-environment (TME).
- Up-regulation of DNMT1 is an early event during mesothelioma development, and levels of DNMT1 over-expression are associated with poor survival in mesothelioma patients.
- Genetic or pharmacologic inhibition of DNMT1 activity induces growth arrest, genomic stress, and apoptosis of mesothelioma cells.
- DNMT1 inhibition can reprogram TMEs thereby promoting more effective antitumor immune responses.
- Decitabine/cedazuridine is an oral DNMT inhibitor which is FDA approved for patients with myelodysplastic syndromes (MDS).
- Conceivably decitabine/cedazuridine therapy can arrest or delay the progression of subclinical/early-stage mesotheliomas in subjects with BAP1 CPDS.
Objective:
-To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Participants with history of germline BRCA1-Associated Protein-1 (BAP1) mutations.
- •Histologically confirmed by NCI LP subclinical, early-stage (Tx-T1) mesotheliomas.
- •Participants with other early-stage BAP1-associated malignancies in addition to subclinical, early-stage mesotheliomas are eligible for study.
- •The extent of the disease (Tx by radiographic imaging) must be insufficient to warrant approved front-line therapies (surgery, chemotherapy, immunotherapy) per standard of care (SOC). Participants with cT1 tumors may be eligible for study if they have been offered and have refused front-line SOC treatment.
- •Age >= 18 years.
- •Evaluable disease as confirmed by minimally invasive (videoscopic) assessment (thoracoscopy and/or laparoscopy) performed at screening (within 8 weeks prior to treatment initiation).
- •Willingness to undergo pre- and post-treatment minimally invasive thoracoscopy and/or laparoscopy to assess treatment response.
- •Willingness to co-enroll on 20C0106 (Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients with BAP1 Tumor Predisposition Syndrome) and/or 06C0014 (Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies) to enable collection/processing of tumor, blood and normal pleura if applicable per PI.
- •ECOG performance status 0 - 1
- •Adequate pulmonary reserve evidenced by FEV1 and DLCO >= 35% predicted on screening pulmonary function testing (PFTs).
- •Oxygen saturation >= 92% on room air by pulse oximetry at screening.
- •Adequate renal, hepatic, and hematopoietic function at screening as defined below:
- •leukocytes >= 3,000/microL
- •absolute neutrophil count >= 1,500/microL (without transfusion or cytokine support within 2 months prior to study treatment initiation)
- •absolute lymphocyte count > 800/microL
- •platelets >=100,000/microL and < 1,200,000/microL
- •prothrombin time (PT) <=2 seconds above the upper limit of normal (ULN)
- •total bilirubin < 1.5 X institutional upper limit of normal OR direct bilirubin <= 1 ULN for participants with total bilirubin > 1.5 ULN
- •serum albumin >= 2.0 mg/dL
- •aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <= 2.5 X institutional ULN
- •creatinine <= 1.6 mg/ml OR creatinine clearance (eGFR) >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.
- •Individuals of child-bearing potential (IOCBP) and those that can father children must agree to use an effective method of contraception (barrier, hormonal, intrauterine device (IUD), surgical sterilization) from the study entry and up to 6 months (IOCBP) or 3 months (those that can father children) after the last dose of the decitabine/cedazuridine.
- •Nursing (including breastfeeding) participants must be willing to discontinue nursing from study treatment initiation through 2 weeks after the last dose of the study drug.
- •The ability of a participant to understand and the willingness to sign a written informed consent document.
排除标准
- •Participants with cancers requiring frontline standard of care treatment.
- •Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to study treatment initiation), myocardial infarction (< 6 months prior to study treatment initiation), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II, serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism.
- •Therapeutic anticoagulation within 2 weeks prior to study treatment initiation.
- •Active Hepatitis A (HAV), Hepatitis B (HBV) (e.g., HBsAg reactive), or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected) at screening.
- •History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
- •Other active infections requiring systemic therapy.
- •Active COVID infection.
- •Major surgery within 4 weeks prior to study treatment initiation.
- •Immunosuppressive medications within 4 weeks prior to study treatment initiation except non-systemic corticosteroids.
- •History of prior treatment with a DNA demethylating agent.
- •Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in IOCBP at screening).
- •Uncontrolled intercurrent illness or situation that would limit compliance with study requirements.
研究组 & 干预措施
1/ Arm 1
Experimental
Decitabine/cedazuridine (35 mg decitabine and 100 mg cedazuridine; PO QD)
干预措施: Decitabine/cedazuridine (Drug)
结局指标
主要结局
To determine stabilization or disease improvement rates in participants with early-stage mesotheliomas arising in the context of BAP1 CPDS following decitabine/cedazuridine treatment
时间窗: baseline, before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit
Assessment of thoracoscopy and/or laparoscopy findings demonstrating stability of evaluable disease or improvement compared to baseline
次要结局
- To determine PFS in participants receiving decitabine/cedazuridine(baseline, after every 6 treatment cycles (Course 1 and Course 2), and until date of progression or last visit ending at the time of the safety visit)
- To evaluate the safety of decitabine/cedazuridine(before each cycle, after every 6 treatment cycles (Course 1 and Course 2), and at the safety visit)
研究者
研究点 (2)
Loading locations...
相似试验
已完成
2 期
Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid LeukemiaAcute Myeloid Leukemia With Myelodysplasia-Related ChangesAdult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2AUntreated Adult Acute Myeloid LeukemiaAcute Myeloid LeukemiaNCT00416598National Cancer Institute (NCI)546
终止
2 期
Decitabine, Cytarabine, GCSF for Refractory AML/MDSMyelodysplasiaLeukemiaNCT00740181Brown University9
终止
2 期
A Study of Oral Decitabine/Cedazuridine in Combination With Magrolimab in Participants With Intermediate- to Very High-Risk Myelodysplastic Syndromes (MDS)Myelodysplastic SyndromesNCT05835011Astex Pharmaceuticals, Inc.2
终止
1 期
Decitabine/Cedazuridine and Enzalutamide for the Treatment of Metastatic Castrate Resistant Prostate CancerCastration-Resistant Prostate CarcinomaStage IV Prostate Cancer AJCC v8Stage IVA Prostate Cancer AJCC v8Stage IVB Prostate Cancer AJCC v8NCT05037500Roswell Park Cancer Institute8
终止
2 期
Decitabine and Midostaurin in Treating Older Patients With Newly Diagnosed Acute Myeloid LeukemiaAcute Myeloid Leukemia (AML) With Multilineage Dysplasia Following Myelodysplastic Syndrome, in AdultsAML (Adult) With 11q23 (MLL) AbnormalitiesAML (Adult) With Del (5q)AML (Adult) With Inv (16) (p13; q22)AML (Adult) With t (16;16) (p13; q22)AML (Adult) With t (8; 21) (q22; q22)Secondary AML (Adult)Untreated AML (Adult)NCT01846624David Iberri13