Phase 1b/2, Multicenter, Dose Escalation Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose and Recommended Phase 2 Dose of DCR-MYC, a Lipid Nanoparticle (LNP)-Formulated Small Inhibitory RNA (siRNA) Oligonucleotide Targeting MYC, in Patients With Hepatocellular Carcinoma (HCC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 21
- 试验地点
- 6
- 主要终点
- Phase 1b: Number of Patients With Adverse Events as a Measure of Safety and Tolerability
研究概览
简要总结
The purpose of this study is to assess the safety and tolerability of the investigational anticancer drug DCR-MYC. DCR-MYC is a novel synthetic double-stranded RNA in a stable lipid particle suspension that targets the oncogene MYC. MYC oncogene activation is important to the growth of many hematologic and solid tumor malignancies. In this study the Sponsor proposes to study DCR-MYC and its ability to inhibit MYC and thereby inhibit cancer cell growth.
详细描述
In this second study in humans, DCR-MYC will be administered by 2 hour intravenous (IV) infusion, once weekly for 2 weeks followed by a rest week (3 weeks = 1 cycle), to patients with hepatocellular carcinoma who are either sorafenib-refractory, sorafenib-intolerant despite dose reduction and best supportive care, or for whom neither sorafenib nor other suitable therapy is available. During the Phase 1b portion of the study, the highest safe dose of DCR-MYC that can be administered will be identified. In addition, the pharmacokinetic (PK) profile, potential pharmacodynamic (PD) effects, as well as the preliminary antitumor activity of DCR-MYC will be evaluated. During the Phase 2 portion of the study, up to 30 patients will be treated at the MTD identified in Phase 1b in order to further evaluate safety and tolerability, as well as assess the antitumor activity, of DCR-MYC.
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
- •Male or female patients, > 18 years of age (in Singapore > 21 years or > 18 years with consent of guardian).
- •Patients with documented (histologically- or cytologically-proven) HCC, with at least 1 measureable lesion > 10 mm (excluding bone metastases). If the measurable lesion(s) is in the liver, it either should not have been treated previously with loco-regional therapy, or there must be demonstrated progression of the lesion following previous loco-regional therapy.
- •Patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor.
- •Patients who are either refractory to or intolerant of sorafenib despite dose reduction and best supportive care, or patients who do not have access to sorafenib or other suitable therapy for HCC.
- •Patients with underlying hepatic cirrhosis must have a current cirrhosis status of Child-Pugh Class A (i.e., score of 5-6) without encephalopathy.
- •Phase 1b MTD Biopsy Cohort: Patients with primary or metastatic tumor site(s) considered safely accessible for biopsy and consenting to undergo pre- and post-dosing tumor biopsies.
- •Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an anticipated life expectancy of ≥ 3 months.
- •Patients, both male and female, who are either not of childbearing potential or who agree to use a medically effective method of contraception during the study and for 3 months after the last dose of study drug.
- •Patients with the ability to understand and give written informed consent for participation in this trial, including all evaluations and procedures as specified by this protocol.
- •Exclusion Criteria (Patients):
- •Women who are pregnant or lactating; women of child-bearing potential (WOCBP), and fertile men with a WOCBP-partner not using and not willing to use a medically effective method of contraception.
- •Patients with known central nervous system (CNS) or leptomeningeal metastases not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.
- •Patients with mixed histology cholangiocarcinoma and HCC, or fibrolamellar variant HCC.
- •Patients with any of the following hematologic abnormalities at baseline:
- •Hemoglobin < 8.5 g/dL
- •Absolute neutrophil count < 1,500 per mm3
- •Platelet count < 75,000 per mm
- •Patients with any of the following serum chemistry abnormalities at baseline:
- •Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution
- •AST or ALT > 5 × the ULN for the institution
- •Serum creatinine > 1.5 × the ULN for the institution
- •Patients with the following coagulation parameter abnormality at baseline:
- •INR > 1.7 × ULN for the institution
- •Patients with:
- •A history of deep vein thrombosis (DVT) or pulmonary embolism (PE), within 6 months prior to first study drug administration; patients receiving systemic anti-coagulation for prophylactic or therapeutic reasons
- •Active uncontrolled bleeding or a known bleeding diathesis
- •Patients with:
- •Esophageal or gastric variceal bleeding within 2 months prior to first study drug administration; patients with a history of variceal bleeding between 2 and 12 months prior to first study drug administration should have undergone adequate treatment and be considered clinically stable in the opinion of the investigator
- •A history of symptomatic ascites requiring paracentesis within the past 3 months or any encephalopathy requiring hospitalization or medication within the past 3 months
- •Portal-caval shunts
- •Patients with a significant cardiovascular disease or condition, including:
- •Congestive heart failure currently requiring therapy
- •Need for antiarrhythmic medical therapy for a ventricular arrhythmia
- •Severe conduction disturbance (i.e., 3rd degree heart block)
- •Angina pectoris requiring therapy
- •Known left ventricular ejection fraction (LVEF) < 50% by MUGA or echocardiogram
- •QTc interval > 450 msec in males, or > 470 msec in females
- •Uncontrolled systemic hypertension (per the Investigator's discretion)
- •Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) Functional Criteria
- •Myocardial infarction within 6 months prior to first study drug administration
- •Patients with a known or suspected hypersensitivity to any of the components of lipid nanoparticle-formulated DCR-MYC; patients with a known sensitivity to cremophor (found with paclitaxel and other formulations).
- •Patients with an estimated daily alcohol intake greater than 80 g/day.
- •Patients having undergone previous organ transplantation (e.g., liver transplantation) requiring immunosuppression; patients on long-term immunosuppressive therapy.
- •Patients with a known history of human immunodeficiency virus (HIV) seropositivity.
- •Patients with any other serious/active/uncontrolled infection, with the exception of chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection; any infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first study drug administration.
- •Patients with inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy.
- •Patients with inadequate recovery from any previous surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to first study drug administration.
- •Patients with an active second malignancy or history of another malignancy within the last 3 years, with the exception of:
- •Treated, non-melanoma skin cancers
- •Treated CIS of the breast or cervix
- 另有 17 项未显示
排除标准
- 未提供
研究组 & 干预措施
DCR-MYC
Patient groups (cohorts) will receive a single dose level of DCR-MYC; the dose level of DCR-MYC will be increased in subsequent cohorts
干预措施: DCR-MYC (Drug)
结局指标
主要结局
Phase 1b: Number of Patients With Adverse Events as a Measure of Safety and Tolerability
时间窗: Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
Part A: 3 patient cohorts with 50% dose increase between cohorts until study drug-related dose-limiting toxicity (DLT) during Cycle 1, then expand to 6 patients and move to Part B. Part B: 3 to 6 patient cohorts with 25% dose increase between cohorts until \> 1 study drug-related DLT, then stop escalation. Expand MTD cohort to 12 patients; tumor biopsies to be performed in this Phase 1b MTD Biopsy Cohort (6 patients).
Phase 2: Patients With Adverse Events as a Measure of Safety and Tolerability
时间窗: Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
Up to 30 patients in the Phase 2 MTD Expansion Cohort (to be treated at the MTD identified in Phase 1b); further evaluation of safety and tolerability.
Phase 2: Preliminary Antitumor Activity
时间窗: After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued
Up to 30 patients in the Phase 2 MTD Expansion Cohort (to be treated at the MTD identified in Phase 1b); evaluation for evidence of objective response or disease stabilization.
次要结局
- DCR-MYC Biological Activities (Phase 1b Only)(Cycle 1 and 2)
- Cmax (ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8(Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4)
- Tmax (Hr) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8(Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4)
- AUClast_D (hr*kg*ng/mL/mg) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8(Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4)
- Cmax_D (kg*ng/mL/mg) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8(Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4)
- AUClast (hr*ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8(Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4)