NCT03179943进行中（未招募）2 期
GU-114: Overcoming Checkpoint Inhibitor Resistance With Epigenetic Therapy in Urothelial Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 21
- 试验地点
- 3
- 主要终点
- Objective Response Rate (RECIST v 1.1) in Phase II
研究概览
简要总结
This is a single arm Phase II study with a safety run-in to identify the recommended phase II dose of the combination therapy of atezolizumab and guadecitabine. Patients with recurrent/advanced urothelial carcinoma (stage IV) who had previously progressed on check-point inhibitor therapy with PD-1 or PD-L1 targeting agents are eligible for this study. After a dose that is safe and tolerable has been established, a dose expansion phase (Phase II) will begin. This study will enroll a total of 4 to 53 patients depending upon the number of patients treated in the safety run-in phase and the number of subjects replaced during the phase II portion.
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
- •Patients must have histologically confirmed urothelial carcinoma that is advanced or metastatic.
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1 and ≥ 1 site safe for biopsy.
- •Patient must agree to provide fresh biopsy specimens and peripheral blood samples at the time of screening and during the study.
- •Patients must have received or be ineligible for platinum based chemotherapy and must have received at least one line of therapy with a PD-L1 or PD-1 targeting agent.
- •Age > 18 years.
- •ECOG performance status ≤ 2
- •Life expectancy ≥ 12 weeks
- •Patients must have normal organ and marrow function as defined below
- •Leukocytes > 3,000/mcL
- •Absolute neutrophil count > 1,500/mcL
- •Platelets > 100,000/mcL
- •Hemoglobin > 9 g/dl (blood transfusion is allowed to meet the eligibility criteria as long as post transfusion hemoglobin is maintained at ≥9.0 g/dL for 7 days or longer)
- •Total bilirubin ≤ 2.5 x institutional upper limit of normal (ULN).
- •AST/ALT (SGOT/SGPT) < 2.5 times institutional normal limits unless liver metastases are present in which case AST and ALT must be ≤ 5 x IULN.
- •Creatinine within normal institutional limits OR
- •Creatinine clearance > 30 Ml/min (Cockcroft-Gault formula or measured with 24h urine)
- •INR or PTT/PT ≤ 1.5 ULN unless patient is on stable therapeutic dose of warfarin
- •Ability to understand and willingness to sign a written informed consent and HIPAA consent document
- •Women of child bearing potential and men must agree to remain abstinent or use adequate contraception (failure rate <1%) for the duration of study and for 90 days after the completion of the therapy.
排除标准
- •Patients who have had anti-cancer therapy within 2 weeks prior to entering the study.
- •Patients receiving any other investigational agents
- •Patients with active or untreated CNS disease. Patients previously treated for CNS disease must be asymptomatic and must not be using steroids for at least 4 weeks prior to starting the study treatment.
- •Patients with active auto-immune disease requiring immunosuppressive medication.
- •Patients treated with systemic immunostimulatory agents (such as interferons, IL 12) within 6 weeks of the start of the treatment or 5 half-lives of the drug, whichever is shorter.
- •Treatment with systemic corticosteroids within 2 weeks prior to the start of the treatment. Patients that require inhaled or low-dose corticosteroids for COPD or asthma, mineralocorticoids are allowed.
- •Patients with active malignancies in addition to urothelial carcinoma.
- •Patients with prior treatment with hypomethylating agents.
- •History of leptomeningeal disease
- •Prior allogeneic stem cell or solid organ transplant.
- •Uncontrolled effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
- •Uncontrolled symptomatic hypercalcemia (>1.5mmol/L ionized calcium or calcium > 12mg/dl or corrected serum calcium > ULN)
- •Mean QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 3 ECGs using Frediricia's correction.
- •Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1 except for endocrine AEs managed with replacement therapy. Any other AEs unresolved toxicities grade 2 or more from previous anti-cancer therapy, except alopecia, peripheral neuropathy or non-clinically significant lab abnormalities.
- •Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to the start of the study treatment.
- •Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis)
- •History of severe allergic, anaphylactic or hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterations), drug-induced pneumonitis or idiopathic pneumonitis or evidence of interstitial lung disease or active non-infectious pneumonitis.
- •Active tuberculosis
- •Known hypersensitivity to Chinese hamster ovary cell products or any of the study drugs.
- •Administration of a live, attenuated vaccine within 4 weeks of the start of treatment or anticipation that such a live, attenuated vaccine will be required during the study.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Known HIV-positive patients on combination antiretroviral therapy are ineligible.
- •Known history of HBV or HCV infection.
- •Pregnant or breast feeding.
研究组 & 干预措施
Atezolizumab + Guadecitabine
Experimental
干预措施: Atezolizumab (Drug)
Atezolizumab + Guadecitabine
Experimental
干预措施: Guadecitabine (Drug)
结局指标
主要结局
Objective Response Rate (RECIST v 1.1) in Phase II
时间窗: 2 years
Maximum tolerated dose of Guadecitabine in combination of Atezolizumab in safety run-in phase
时间窗: 2-3 months
Dose de-escalation study based on standard 3+3 design will be conducted to test two dose levels of guadecitabine: 45mg/m2 and 36mg/m2 to determine MTD
次要结局
- Overall Survival(2 years)
- Progression Free Survival(2 years)
研究者
研究点 (3)
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