NCT02110563终止1 期
Phase I, Multicenter, Cohort Dose Escalation Trial to Determine the Safety, Tolerance, and Maximum Tolerated Dose of DCR-MYC, a Lipid Nanoparticle (LNP)-Formulated Small Inhibitory RNA (siRNA) Oligonucleotide Targeting MYC, in Patients With Refractory Locally Advanced or Metastatic Solid Tumor Malignancies, Multiple Myeloma, or Lymphoma
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company6 个研究点 分布在 1 个国家目标入组 50 人开始时间: 2014年4月最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 50
- 试验地点
- 6
- 主要终点
- 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 first-in human study, 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 either solid tumor malignancies, multiple myeloma, or non-Hodgkins lymphoma that have not responded to previous treatment. 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 antitumor activity of DCR-MYC will be evaluated.
There will be 2 expansion cohorts at the maximum tolerated dose (MTD) (or highest safe dose identified for further study which may be lower):
- Biopsy Cohort: 6 patients, tumor biopsies to be performed pre-dosing and Cycle 2/Day 11; same assessments as dose escalation cohorts
- PNET Cohort: Up to 20 patients with pancreatic neuroendocrine tumors; same assessments as dose escalation cohorts, however fewer PD (cytokine) assessments and no PK assessments
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 at the time of obtaining informed consent.
- •Patients with a documented solid tumor malignancy that is locally advanced or metastatic; patients with documented multiple myeloma or non-Hodgkin's lymphoma.
- •Patients with a malignancy that is either refractory to standard therapy or for which no standard therapy is available.
- •Patients with a malignancy that is currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor.
- •Dose escalation portion of study: Patients with measurable or non-measurable disease according to standard response criteria .
- •MTD Biopsy Cohort ONLY: Patients with measurable disease with primary or metastatic tumor site(s) considered safely accessible for biopsy; patients must consent to undergo 2 tumor biopsies.
- •MTD PNET Cohort ONLY: Patients with advanced (unresectable or metastatic), histologically-confirmed low or intermediate grade PNET according to the World Health Organization (WHO) 2010 classification. Patients with neuroendocrine tumors (e.g., gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary is strongly suspected are also eligible. Patients must also have:
- •A Ki-67 proliferation index < 20%
- •Demonstrated radiological evidence of disease progression during or following the last treatment regimen (based on CT, MRI, or Octreoscan®)
- •Measurable disease according to RECIST v1.1 (determined by CT or MRI). Any lesions which have been subjected to percutaneous therapies or radiotherapy should not be considered measureable, unless the lesion has clearly progressed (per RECIST v1.1) since the procedure.
- •Received < 2 prior systemic treatments for PNET, at least one of which must have been an FDA-approved targeted therapy for PNET (i.e., sunitinib [Sutent®] or everolimus [Afinitor®]). Treatment with a somatostatin analog (SSA) will not be considered as a systemic treatment for the purposes of eligibility.
- •Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, 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 leukemia (any form) or myelodysplastic syndromes.
- •MTD PNET Cohort ONLY: Patients with poorly differentiated, high grade (grade 3) neuroendocrine carcinoma, as well as patients with adenocarcinoid, goblet cell carcinoid, or small cell carcinoma, or PNET patients with a Ki-67 proliferation index > 20 %.
- •Patients with any of the following hematologic abnormalities at baseline:
- •Absolute neutrophil count < 1,500 per mm3
- •Platelet count < 100,000 per mm3
- •Patients with any of the following serum chemistry abnormalities at baseline:
- •Total bilirubin > 1.5 × the ULN for the institution
- •AST or ALT > 3 × the ULN for the institution (> 5 × if due to hepatic involvement by tumor)
- •Creatinine > 1.5 × ULN for the institution
- •Patients with any of the following coagulation parameter abnormalities at baseline:
- •PT (INR) > 1.5 × ULN for the institution
- •PTT > 1.5 × ULN for the institution
- •Patients with:
- •Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, 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 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 (e.g., 3rd degree heart block)
- •Angina pectoris requiring therapy
- •Known left ventricular ejection fraction < 50% by MUGA or echocardiogram
- •QTc interval > 450 msec in males, or > 470 msec in females
- •Uncontrolled hypertension (per the Investigator's discretion)
- •Class III or IV cardiovascular disease according to the New York Heart Association's 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 history of human immunodeficiency virus or active infection with hepatitis B virus or hepatitis C virus.
- •Patients with any other serious/active/uncontrolled 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 prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to first study drug administration.
- •Patients with any other life-threatening illness, significant organ system dysfunction, or clinically significant laboratory abnormality, which, in the opinion of the Investigator, would either compromise the patient's safety or interfere with evaluation of the safety of the study drug.
- •Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary study-related evaluations.
- •Patients with the inability or with foreseeable incapacity, in the opinion of the Investigator, to comply with the protocol requirements.
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排除标准
- 未提供
研究组 & 干预措施
DCR-MYC
Experimental
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
Number of patients with adverse events as a measure of safety and tolerability
时间窗: Cycle 1 (3 weeks), longer if DRC-MYC is continued; with 30 days follow-up after last dose
Part A: 1 patient cohorts with 100% dose increase between cohorts until \>/= Grade 2 study drug-related toxicity during Cycle 1, then expand to 3 patients and move to Part B. Part B: 3 patient cohorts with 50% dose increase between cohorts until study drug-related DLT during Cycle 1, then expand to 6 patients and move to Part C. Part C: 3 to 6 patient cohorts with 25% dose increase between cohorts until \> 1 study drug-related DLT, then stop escalation and expand previous MTD cohort to 18 patients.
次要结局
- DCR-MYC levels in blood(Cycle 1; Week 1 and Week 2)
- DCR-MYC biological activities(Cycle 1 and Cycle 2)
- Preliminary antitumor activity(After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued)
研究者
研究点 (6)
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