Phase I, Open-label Study to Investigate Safety, Tolerability, PK, and PD of EMD 525797 After Single and Repeated Dosing at Different Dose Levels in Subjects With Hormone-resistant Prostate Cancer With Bone Mets and Progressive Disease Following Prior CTX
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 4
- 主要终点
- Observed Maximum Serum Concentration (Cmax) of EMD 525797 After First Infusion
研究概览
简要总结
This study is intended to test an experimental new drug called, EMD 525797 (Study Drug). This drug is not yet approved for sale and has only been tested in a small number of people to date (prior to this study starting another research study was carried out involving 37 healthy volunteers receiving the Study Drug). Until more is known about this Study Drug, it can only be used in research studies.
This research study is planned to answer important questions about how the Study Drug is tolerated and how it may work in patients with prostate cancer with bone metastases.
This is a small study which is expected to include 24 patients, and will be conducted in approximately 3 hospitals in Germany and 1 hospital in Brussels, Belgium. The study will last until the last patient has had their last study visit which is expected to be about 18 months in total.
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
- Male
- 接受健康志愿者
- 否
入选标准
- •Provision of signed written informed consent
- •Age superior or equal to 18 years
- •Subjects with histological or cytologically proven prostate cancer with evidence of bone metastases on bone scans or CT / MRI after prior chemotherapy with e.g. taxane or mitoxantrone Patients should have undergone bilateral orchiectomy or should be on continuous androgen deprivation therapy with a gonadotropin releasing hormone agonist or antagonist and should have stopped any anti-androgen therapy for at least 4 weeks before inclusion in the study. Patients should be either on stable (i.e., since at least 3 months) ongoing therapy with a bisphosphonate or without any bisphosphonate therapy. Initiation of a bisphosphonate therapy within this time period prior the study or during the study is not allowed. Total serum testosterone should be less than 50 ng/dL or 1.7 nmol/L.
- •Evidence of progressive disease, defined by at least two PSA values above the individual nadir level with an increase of at least 10% each determined at a minimum interval of 2 weeks before screening examination. Presence of a measurable lesion is not required for study entry. Nodal (in lymph nodes superior or equal to 2cm) or visceral progression is sufficient for trial entry independent of PSA.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at study entry and an estimated life expectancy of at least 3 months.
- •Adequate hematological function, defined by white blood cell count (WBC) greater than or equal to 3 x 109/L with absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, and lymphocyte count greater than or equal to 0.5 x 109/L; platelet count greater than or equal to 100 x 109/L; and hemoglobin greater than or equal to 9 g/dL.
- •Adequate hepatic function defined by total bilirubin level less than or equal to 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than or equal to 2.5 x ULN; or, for subjects with documented metastatic disease to the liver, AST and ALT levels less than or equal to 5 x ULN.
- •Adequate renal function defined by serum creatinine less than 1.5 mg/dL.
- •Effective contraception. If the risk of conception exists, pregnancy has to be avoided during the study (SCR to EOS) as well as during at least 3 month after last dosing using an effective contraception method (e.g. double barrier method)
排除标准
- •Any systemic cytotoxic cancer treatment within 4 weeks before treatment with EMD
- •Acute pathologic fracture, spinal cord progression, hypercalcemia (within 4 weeks period prior to screening).
- •Radiotherapy to bone lesions, orthopaedic surgery, or any investigational drug in the 30 days before the start of treatment in this study and during treatment period, and/or biopsies involving bone within 2 weeks before the start of treatment in this study.
- •Supraphysiologic doses of steroids (defined as superior or equal to 7.5 mg of prednisone equivalents per day).
- •Previous treatment with anti-integrin therapy.
- •Confirmed or clinically suspected brain metastases.
- •Known hypersensitivity reactions to any of the components of the study medication.
- •History of allergic reactions to other monoclonal antibody (mAb) therapy.
- •Uncontrolled hypertension (systolic greater or equal to 160 mmHg, diastolic greater than or equal to 100 mmHg).
- •Current history of chronic daily aspirin therapy (ASS at doses inferior or equal to 100 mg is permitted), bleeding disorders and/or history of thromboembolic events (history of superficial thrombophlebitis is not an exclusion criterion); thrombolytics or oral or parenteral anticoagulants within 10 days prior to study start and during treatment period.
- •Severe peripheral vascular disease or ulceration.
- •Unstable angina pectoris, or myocardial infarction within 6 months before start of study treatment, clinical significant abnormal ECG at screening
- •Known alcohol or drug abuse.
- •Participation in another clinical trial within the past 30 days before start of study treatment.
- •Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
- •Ongoing uncontrolled infections, including active or chronic hepatitis B or C, ongoing HIV infection.
- •Legal incapacity or limited legal capacity.
- •All other significant diseases which, in the opinion of the Investigator, might impair the subject's tolerance of study treatment.
研究组 & 干预措施
EMD 525797
干预措施: EMD 525797 (Biological)
结局指标
主要结局
Observed Maximum Serum Concentration (Cmax) of EMD 525797 After First Infusion
时间窗: pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1
Apparent Volume of Distribution During Terminal Phase (Vz) of EMD 525797 After First Infusion
时间窗: pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as = Dose/(AUC0-inf \*λz) after first infusion. Where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.
Trough Serum Concentration (Ctrough) Of EMD 525797 at Week 1
时间窗: pre-dose at Week 1
Ctrough is the concentration prior to study drug administration.
Trough Serum Concentration (Ctrough) Of EMD 525797 at Week 3
时间窗: pre-dose at Week 3
Ctrough is the concentration prior to study drug administration.
Number of Subjects With Dose Limiting Toxicity (DLT)
时间窗: Baseline up to 6 weeks
DLT was defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 3.0 as any Grade 3 or 4 hematological or non-hematological toxicity occurring at any dose level until the end of Week 6, and suspected to be reasonably related to the investigational product by the Investigator and/or Sponsor except for allergic/ hypersensitivity reactions and any Grade 3/4 out-of-range laboratory values without any clinical correlate, which were reversible within 7 days.
Observed Maximum Serum Concentration (Cmax) of EMD 525797 After Third Infusion
时间窗: pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 5
Area Under the Serum Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) After First Infusion
时间窗: pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1
Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule.
Total Body Clearance of Drug From Serum (CL) After First Infusion
时间窗: pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Total body clearance of drug from serum, calculated as CL = dose/AUC0-inf. Where AUC0-inf is area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above lower limit of quantification (LLQ) and λz is elimination rate constant.
Trough Serum Concentration (Ctrough) Of EMD 525797 at Week 5
时间窗: pre-dose at Week 5
Ctrough is the concentration prior to study drug administration.
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs
时间窗: Baseline up to 534 days
An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs.Treatment-related are events which had causal relationship to study drug as assessed by the Investigator and were suspected to be reasonably related to the study drug.
次要结局
- Serum Levels of Interleukin 6 (IL-6) and Interleukin 8 (IL-8)(Week 1 up to a maximum of 56 days)
- C-Reactive Protein Levels(Week 1 up to a maximum of 56 days)
- Observed Minimum Serum Concentration (Cmin) of EMD 525797 After Third Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 5)
- Number of Subjects With Positive Anti-EMD 525797 Antibodies(Week 1, 3, 5, 8, 9)
- Apparent Terminal Half-life (t1/2) of EMD 525797 After First Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1)
- Elimination Rate Constant (λz) of EMD 525797 After First Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1)
- Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval (AUCtau) of EMD 525797 After Third Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96,168, 336 hours post third infusion at Week 5)
- Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of EMD 525797 After First Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1)
- Progression-free Survival (PFS) as Per Prostate Cancer Clinical Trials Working Group 1 (PCWG1) and Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria(Baseline up to 394 days)
- Time to Reach Observed Serum Concentration (Tmax) After First Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1)
- Time to Reach Observed Serum Concentration (Tmax) After Third Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 5)
- Peak Trough Fluctuation Over One Dosing Interval at Steady State (%PTF) of EMD 525797 After Third Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 5)
- Accumulation Ratio Of Cmax (R_Cmax)(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1 and Week 5)
- Number of Subjects With Best Overall Response (BOR)(Week 6, Week 19, Overall (Baseline Up to 394 days))
- Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score vs. Best Post-baseline Score(Baseline up to 394 days)
- Average Serum Concentration at Steady State (Cav) of EMD 525797 After Third Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168, 336 hours post third infusion at Week 5)
- Apparent Volume of Distribution at Steady State (Vss) of EMD 525797 After Third Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 5)
- Area Under the Serum Concentration-time Curve Within One Complete Dosing Interval (AUCtau) of EMD 525797 After First Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96 and 168 hours post-infusion at Week 1)
- Mean Residence Time of Drug in the Body (MRT) of EMD 525797 After First Infusion(pre-dose, end of infusion, 4, 8, 24, 48, 96, 168 and 336 hours post-infusion at Week 1)
- Accumulation Ratio of AUC (R_AUC)(pre-dose, end of infusion, 4, 8, 24, 48, 96,168 hours post-infusion at Week 1 and pre-dose, end of infusion, 4, 8, 24, 48, 96, 168, 336 hours post third infusion at Week 5)
- Time to Progression (TTP)(Baseline up to disease progression up to a maximum of 13.1 months)
- Total Pain Score Using Brief Pain Inventory-Short Form (BPI-sf)(Screening; Baseline; Week 3, 5, 7; Follow-up (FUP) Week 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75; End of treatment (EOT; maximum up to 380 days) and EOS (maximum up to 394 days))
- Maximum Percent Change From Baseline in Prostate Specific Antigen (PSA) Level(Baseline up to 394 days)
- Minimum Percent Change From Baseline in PSA Level(Baseline up to 394 days)
- Number of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score vs. Worst Post-baseline Score(Baseline up to 394 days)