Phase I Dose Escalation Study Evaluating the Safety and Tolerability of PankoMab-GEX™ in Patients With Advanced, TA-MUC1 Positive Solid Malignancies Who Are Not Longer Eligible for Standard Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 74
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-Emergent Adverse Events assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 3.0
研究概览
简要总结
Prospective, open label, dose escalating, multicenter, phase I study measuring the safety, tolerability, and pharmacokinetics of PankoMab-GEX™ after intravenous administration in patients with locally advanced or metastatic solid cancers refractory to standard treatment. The effect of PankoMab-GEX™ on the development of antibodies and tumor response was also evaluated.
详细描述
Male or female patients of age 18 years or older with a histologically-confirmed, tumor-associated mucin 1 (TA-MUC1) positive, measurable or non-measurable solid tumor who had failed standard therapy and for whom no standard therapy was available.
Open-label, non-randomized, inter-patient dose escalation, multi-center study in a 3 + 3 design.
Patients received PankoMab-GEX™ treatment until disease progression or until the treatment was no longer tolerated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female and age ≥ 18 yrs
- •Histologically-confirmed TA-MUC1 positive measurable or non-measurable solid tumors according to RECIST criteria who failed standard therapy and for whom no further standard therapy is available (TA-MUC1 positivity assessed by PankoMab-GEX™ staining in immunohistology of the tumor).
- •Failure of standard therapy or non-availability of standard therapy
- •Patients must have received at least 1 standard chemotherapy during the course of the tumor disease
- •All therapies must be completed 6 weeks (therapeutic monoclonal antibodies) or 4 weeks (all other anti-cancer agents) before start of study treatment and patients must have recovered from all prior therapy toxicities to at least CTCAE grade 1
- •Performance status: Eastern Cooperative Oncology Group (ECOG) 0-1 and estimated life expectancy of > 3 months
- •Adequate organ function as assessed by the following laboratory parameters within 14 days prior to study drug application:
- •Bone marrow function: hemoglobin ≥ 100 g/L; white blood cell count (WBC) ≥ 3.0 x 10^9/L; absolute neutrophil count (ANC) ≥ 1.5x 10^9/L; platelet count ≥ 100 x 10^9/L
- •Hepatic: aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 2.5 times upper limit of normal (ULN) (≤ 5 x ULN if hepatic metastases present); bilirubin ≤ 1.5 x ULN; alkaline phosphatase ≤ 5.0 times upper limit of normal (ULN)
- •Renal: Calculated creatinine clearance > 80 ml/min using the Modification of Diet in Renal Disease (MDRD) formula according to Levey 2005: Glomerular filtration rate (GFR) (ml/min/1.73 m²) = 186 x (serum creatinine /0,95)^-1.154 x (age)^-0.203 x (0.742 females) x (1.21 in black patients)
- •Patients of both genders with procreative potential must use effective contraception while enrolled in the study and for at least 6 weeks after the last study drug infusion
- •Written informed consent must be obtained prior to conducting any study-specific procedures
排除标准
- •Antibody-based immunotherapy within 6 weeks and chemotherapy, radiation or other anti-cancer therapies within 4 weeks prior to study enrolment
- •Any investigational agents at the study enrolment
- •Concurrent anti-tumor therapy or concurrent immunotherapy
- •Concurrent systemic steroids except topical (inhaled, topical, nasal), replacement therapy for the last 28 days. Steroids at low and stable dose (up to 20 mg prednisone) given for chronic disease are also permitted
- •History of allergic reactions to previous antibody therapy
- •Major surgery within 4 weeks prior entering the study and/or incomplete recovery from surgery or planned major surgery
- •Documented history of active autoimmune disorders requiring systemic immunosuppressive therapy such as sarcoidosis, lupus erythematosus, rheumatoid arthritis, glomerulonephritis or systemic vasculitis (except autoimmune thyroiditis with only thyroid hormone replacement and stable disease >1 year)
- •Primary or secondary immune deficiency
- •Clinically active infections > CTCAE grade 2
- •Prior allergic reaction to a monoclonal antibody (e.g. Trastuzumab, Cetuximab or Bevacizumab).
- •Active hepatitis B or C; human immunodeficiency virus (HIV) seropositivity
- •Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the cervix. Patients with a previous malignancy but without evidence of disease for ≥3 years will be allowed to enter the study.
- •Uncontrolled medical condition considered as high risk for the treatment with an investigational drug including unstable diabetes mellitus, vena-cava-syndrome, chronic symptomatic respiratory disease.
- •Brain metastasis or leptomeningeal involvement
- •Symptomatic congestive heart failure (New York Heart Association [NYHA] 3 or 4); unstable angina pectoris within 6 months prior to enrollment; significant cardiac arrhythmia, history of stroke or transient ischemic attack within 1 year or left ventricular ejection fraction (LVEF) below the institutional range of normal on a baseline multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
- •History of seizures, encephalitis or multiple sclerosis
- •History of deep vein thrombosis and/or thromboembolic events within the past 6 months before entering the study and/or requiring anticoagulation therapy
- •Evidence or history of bleeding diathesis or coagulopathy
- •Active drug abuse or chronic alcoholism
- •Pregnancy or breastfeeding
研究组 & 干预措施
PankoMab-GEX™, 3-weekly
application, q3w
干预措施: PankoMab-GEX™ (Drug)
PankoMab-GEX™, 2-weekly
application q2w
干预措施: PankoMab-GEX™ (Drug)
PankoMab-GEX™, weekly
application q1w
干预措施: PankoMab-GEX™ (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 3.0
时间窗: Until 28±2 days following the last infusion
Adverse events coded using Medical Dictionary for Regulatory Activities (MedDRA) version 13.1
Incidence of Treatment-Emergent abnormal clinical laboratory parameters assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 3.0
时间窗: Until 28±2 days following the last infusion
Analyzed in local clinical laboratories
Changes in corrected QT interval (QTc) duration
时间窗: Until 28±2 days following the last infusion
based on Electrocardiograms (ECG)
Changes of left ventricular ejection fraction (LVEF)
时间窗: Until 28±2 days following the last infusion
based on Multiple Gated Acquisition (MUGA) scan or Echocardiogram (ECHO)
Eastern Cooperative Oncology Group (ECOG) Performance Status
时间窗: Until 28±2 days following the last infusion
The ECOG Scale of Performance Status describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.). The scale comprises six grades: 0 Fully active, able to carry on all pre-disease performance without restriction 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours 3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 5. Dead
次要结局
- Pharmacokinetics (PK): Peak Plasma Concentration (Cmax)(Assessment prior to and 2 min before the end of first infusion, 1 hr and 3 hrs after end of first infusion and 24 hrs after start of first infusion, on Day 2, Day 4, Day 7, Day 14, and then prior to and after end of each infusion up to 15 weeks)
- Pharmacokinetics (PK): Minimum Drug Concentration (Cmin)(Assessment prior to and 2 min before the end of first infusion, 1 hr and 3 hrs after end of first infusion and 24 hrs after start of first infusion, on Day 2, Day 4, Day 7, Day 14, and then prior to and after end of each infusion up to 15 weeks)
- Pharmacokinetics (PK):Time to reach Cmax (tmax)(Assessment prior to and 2 min before the end of first infusion, 1 hr and 3 hrs after end of first infusion and 24 hrs after start of first infusion, on Day 2, Day 4, Day 7, Day 14, and then prior to and after end of each infusion up to 15 weeks)
- Pharmacokinetics (PK): Area under the curve (AUC)(Assessment prior to and 2 min before the end of first infusion, 1 hr and 3 hrs after end of first infusion and 24 hrs after start of first infusion, on Day 2, Day 4, Day 7, Day 14, and then prior to and after end of each infusion up to 15 weeks)
- Pharmacokinetics (PK): Apparent terminal serum half-life (t1/2)(Assessment prior to and 2 min before the end of first infusion, 1 hr and 3 hrs after end of first infusion and 24 hrs after start of first infusion, on Day 2, Day 4, Day 7, Day 14, and then prior to and after end of each infusion up to 15 weeks)
- To evaluate any immunogenicity(Anti-drug antibodies (ADAs) were to be measured before the first infusion of study medication, prior to the second infusion, 4 weeks and 8 weeks after the last study medication administration.)
- Tumor response: Best observed response(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Tumor response: Objective response rate (ORR)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Tumor response: Clinical benefit rate (CBR)(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Tumor response: Duration of response(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)
- Tumor response: Duration of stable disease(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months)