A PHASE Ib/IIa STUDY OF COMBINATION THERAPY WITH GEMCITABINE AND ATU027 IN SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC PANCREATIC ADENOCARCINOMA
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 29
- 试验地点
- 9
- 主要终点
- Measuring of subject vital signs and body weight
研究概览
简要总结
The purpose of the study is to evaluate a new treatment strategy for advanced pancreatic cancer disease by combining the new investigational medicinal product Atu027 with the standard chemotherapeutic gemcitabine. This combination aims at enhancing gemcitabine´s anti-tumor activity with Atu027.
The objectives of this clinical trial are to evaluate safety and activity of two Atu027 schedules in combination with standard gemcitabine treatment in patients with advanced or metastatic pancreatic adenocarcinoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 84 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Lead-in safety period:
- •Subjects between the age of 18 and 84 years
- •Histologically or cytologically confirmed advanced or refractory cholangiocellular carcinoma, biliary tract cancer, non-small-cell lung carcinoma, duodenal cancer, soft tissue sarcoma, ovarian carcinoma, or another non-pancreatic cancer disease indicated for gemcitabine treatment as determined by the investigator
- •Subjects who have previously received chemotherapy and standard curative or palliative care is not available, not effective, or unlikely to be effective
- •No option for surgical resection or radiation in curative intent
- •Eastern Cooperative Oncology Group (ECOG) performance status assessment of 0 to 2
- •Life expectancy of at least 3 months
- •No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
- •Alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN; ≤5 x ULN for subjects with liver metastases)
- •Aspartate aminotransferase (AST) ≤3.0 x ULN (≤5 x ULN for subjects with liver involvement with cancer)
- •Total bilirubin ≤2.0 x ULN (liver metastasis <5 x ULN)
- •Serum creatinine ≤1.5 x ULN
- •Adequate bone marrow function: subjects should have an absolute granulocyte count of at least 1,500 (x 10e6/L) and platelet count of 100,000 (x 10e6/L) prior to the initiation of a cycle.
- •Prothrombin time-international normalized ratio/partial thromboplastin time (PT-INR/PTT) <1.5 x ULN (subjects who are being therapeutically anti-coagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists). Low-dose aspirin is permitted (≤100 mg daily).
- •Women of childbearing potential must have a negative urine pregnancy test at baseline.
- •Women of childbearing potential and men must be willing to use highly effective contraceptive methods during the course of the study and 6 months after.
- •Subjects must be willing and able (in the opinion of the investigator) to understand the subject information and informed consent form and to comply with the study protocol and procedures.
- •Subjects must be willing and able to give written informed consent.
- •Subjects between the age of 18 and 84 years
- •Subjects with locally advanced or metastatic pancreatic adenocarcinoma stage III/IV indicated for gemcitabine treatment as determined by the investigator
- •No option for surgical resection or radiation in curative intent
- •Histological or cytological documentation of non-hematologic, malignant solid tumor
- •At least one measurable lesion or evaluable disease, as per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status assessment of 0 to 2
- •Life expectancy of at least 3 months
- •No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
- •Alanine aminotransferase (ALT) <=3.0 x upper limit of normal (ULN; <=5 x ULN for subjects with liver metastases)
- •Aspartate aminotransferase (AST) <=3.0 x ULN (<=5 x ULN for subjects with liver involvement with cancer)
- •Total bilirubin <=2.0 x ULN (liver metastasis <=5 x ULN)
- •Serum creatinine <=1.5 x ULN
- •Adequate bone marrow function: subjects should have an absolute granulocyte count of at least 1,500 (x 10e6/L) and platelet count of 100,000 (x 10e6/L) prior to the initiation of a cycle.
- •Prothrombin time-international normalized ratio/partial thromboplastin time (PT INR/PTT) <1.5 x ULN (subjects who are being therapeutically anti-coagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists). Low-dose aspirin is permitted (≤100 mg daily).
- •Women of childbearing potential must have a negative urine pregnancy test at baseline.
- •Women of childbearing potential and men must be willing to use highly effective contraceptive methods during the course of the study and 6 months after.
- •Subjects must be willing and able (in the opinion of the investigator) to understand the subject information and informed consent form and to comply with the study protocol and procedures.
- •Subjects must be willing and able to give written informed consent.
排除标准
- •Lead-in safety period:
- •History of cardiac disease; congestive heart failure >New York Heart Association (NYHA) functional classification system Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina, or ventricular cardiac arrhythmias requiring anti-arrhythmic therapy
- •Poorly controlled diabetes defined as hemoglobin A1c (HbA1c) >=7%
- •Poorly controlled hypertension, defined as systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg, despite optimal medical management
- •Poorly controlled seizure disorder
- •Subjects undergoing renal dialysis
- •Known hypersensitivity to the study drugs or active substances or excipients of the preparations
- •Pregnant or breast feeding
- •Known hepatitis B or C or human immunodeficiency virus (HIV) infection (if documented in the subject's record
- •Previous participation in this study
- •Current or previous (within 30 days of enrolment) treatment with another investigational drug or participation in another clinical study.
- •Subject is a relative of, or staff directly reporting to the investigator.
- •Subject is an employee of the sponsor.
- •Subject is committed under official or judicial order.
- •Any other reason that the investigator considers makes the subject unsuitable to participate
- •History of cardiac disease; congestive heart failure >New York Heart Association (NYHA) functional classification system Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina, or ventricular cardiac arrhythmias requiring anti-arrhythmic therapy
- •Poorly controlled diabetes defined as hemoglobin A1c (HbA1c) >=8%
- •Poorly controlled hypertension, defined as systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg, despite optimal medical management
- •Poorly controlled seizure disorder
- •Subjects undergoing renal dialysis
- •Anticancer chemotherapy or immunotherapy during the study or before first study treatment. Subjects with recurrent disease after adjuvant treatment not progression-free for at least 6 months.
- •Radiotherapy to target lesions during study or before study start
- •Known hypersensitivity to the study drugs or active substances or excipients of the preparations
- •Pregnant or breast feeding
- •Known hepatitis B or C or human immunodeficiency virus (HIV) infection (if documented in the subject's record
- •Previous participation in this study
- •Current or previous (within 30 days of enrolment) treatment with another investigational drug or participation in another clinical study.
- •Subject is a relative of, or staff directly reporting to the investigator.
- •Subject is an employee of the sponsor.
- •Subject is committed under official or judicial order.
- •Any other reason that the investigator considers makes the subject unsuitable to participate
研究组 & 干预措施
Lead in safety period
Cohort of three subjects with non-pancreatic cancer for whom conventional treatment options have failed, will be treated. If one of the subjects in the safety cohort experiences an unacceptable toxicity, the safety cohort is expanded to six subjects.
干预措施: Atu027 & gemcitabine in lead in safety period (Drug)
Treatment arm 1
Subjects with advanced pancreatic cancer will be treated.
干预措施: Atu027 & gemcitabine in treatment arm 1 (Drug)
Treatment arm 2
Subjects with advanced pancreatic cancer will be treated.
干预措施: Atu027 & gemcitabine in treatment arm 2 (Drug)
结局指标
主要结局
Measuring of subject vital signs and body weight
时间窗: At baseline; end of treatment (13 weeks); later on in 4 week intervals till last follow up visit (1 year)
End of treatment visit will be after 13 weeks only when patient is withdrawn after 3 cycles. Additional time frames in arm 1: 8 days after baseline. Additional time frames in arm 2 and safety cohort (cycle 1 only): 4 and 15 days after baseline.
Number of subjects with adverse events
时间窗: Baseline till follow up visit 1 (18 weeks)
Time frame will be 18 weeks if patient will be withdrawn after 3 cycles because of disease progression or toxicity.
Assessment of clinically significant laboratory parameters outside normal range
时间窗: At baseline; at end of treatment (week 13 if patient withdrawn after 3 cycles); at follow up visit 1 (week 18 if patient withdrawn after 3 cycles); at each follow up visit till end of trial (1 year)
Additional time frames in arm 1: During treatment on days 1, 8, 15 of each cycle. Additional time frames in arm 2 and safety cohort (cycle 1 only): During treatment on days 1, 4, 8, 11, 15, 18, 22, 25 of each cycle.
Subject physical examination
时间窗: At baseline; later on in 4 week intervals till last follow up visit (1 year);
Additional time frames in arm 1: 8 days after baseline. Additional time frames in arm 2 and safety cohort (cycle 1 only): 4 and 15 days after baseline.
Maximum concentration (Cmax), area under the curve (AUC), time to maximum concentration (tmax), and half life (t½) of the Atu027 siRNA single strand (A-strand), and of AtuFect01 and the helper lipid DPyPE
时间窗: At end of treatment (week 13 if patient withdrawn after 3 cycles); at follow up visit 1 (week 18 if patient withdrawn after 3 cycles)
Additional time frames in arm 1: During cycles 1 and 2 of treatment on days 1, 8, 15 of each cycle; in cycle 3 and following only on day 1; Additional time frames in arm 2 and safety cohort (cycle 1 only): During the first treatment cycle on days 1, 4, 8, 11, 15, 18; in cycle 3 and following odd numbered cycles only on day 1; in all even numbered cycles no samples are taken. Pharmacokinetics will be assessed in subjects of the safety cohort and in the first 4 subjects per treatment arm.
Performance of 12-lead ECG
时间窗: At baseline; later on in 4 week intervals till end of treatment (13 weeks)
End of treatment visit will be after 13 weeks only when patient is withdrawn after 3 cycles. Additional time frames in arm 1: 8 days after baseline. Additional time frames in arm 2 and safety cohort (cycle 1 only): 4 and 15 days after baseline.
次要结局
- Progression-free survival and overall survival(From baseline in 8 week intervals till end of trial (1 year).)
- Objective response rate(At baseline and in 8 week intervals till end of trial (1 year))
- ECOG performance score(At baseline; at end of treatment (13 weeks if patient withdrawn after 3 cycles); at follow up visit 1 (18 weeks if patient withdrawn after 3 cycles); at each following follow up visit till end of trial (1 year))
- Quality of life(At baseline; at day 1 of all cycles except cycle 1; at end of treatment (week 13 if patient withdrawn after 3 cycles))
- Biomarker response(At baseline; at day 1 of cycle 3; end of treatment (13 weeks if patient withdrawn after 3 cycles); follow up visit 1 (18 weeks if patient withdrawn after 3 cycles))
- Tumor marker response(At baseline; at end of treatment (13 weeks if patient withdrawn after 3 cycles); at follow up visit 1 (18 weeks if patient withdrawn after 3 cycles); at each following follow up visit till end of trial (1 year))