A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI0639 in Adult Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 58
- 试验地点
- 12
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Echocardiogram Evaluations
研究概览
简要总结
This is a first-time-in-human, Phase 1, multicenter, open-label, single-arm, dose-escalation (3+3) study to evaluate the safety, tolerability, antitumor activity, PK and immunogenicity of MEDI0639.
详细描述
This is a first-time-in-human, Phase 1, multicenter, open-label, single-arm, dose-escalation (3+3) study to evaluate the safety, tolerability, antitumor activity, PK, and immunogenicity of MEDI0639 in adult subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy exist. Up to 63 subjects will be enrolled at approximately 3 to 5 study centers in North America.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed solid tumors that are refractory to standard therapy or for which no standard therapy exist
- •Age ≥ 18 years
- •ECOG Performance Status of 0 or 1
- •LVEF (measured by Echocardiogram) > 50%
- •No gastrointestinal bleeding within 1 year of study entry.
- •Adequate organ and marrow function:
- •Hemoglobin ≥ 10g/dL
- •Absolute Neutrophil Count ≥ 1500/mm3
- •Platelet Count ≥ 100,000/mm3
- •AST & ALT ≤ 2.5 x ULN
- •Bilirubin ≤ 1.5 x ULN
- •Cr Cl ≥ 50 mL/min (as determined by the Cockcroft-Gault equation or by 24-hour urine collection)
- •Prior therapy against VEGF or VEGFRs including, but not limited to bevacizumab, sunitinib, sorafenib, pazopanib, motesanib (AMG706), or cediranib (AZD2171), is permitted so long as the agent does not have any known activity against DLL4 and the last dose received s at least 6 weeks prior to first dose of MEDI
- •Life expectancy ≥ 12 weeks
- •Females of childbearing potential must be surgically sterile, have a sterile male partner, be premenarchal or at least 2 years postmenopausal, practice abstinence or otherwise must use 2 effective methods of contraception from the time of initiation of investigational product.
- •Males, unless surgically sterile, must use 2 effective methods of contraception with a female partner and must agree to continue using such contraception for 90 days after the last dose of MEDI0639
排除标准
- •Concurrent enrollment in another investigational clinical study
- •Receipt of any investigational anticancer therapy within 4 weeks prior to the first dose of MEDI0639 or in the case of monoclonal antibodies, 6 weeks prior to the first dose of MEDI0639
- •Concurrent or previous treatment with inhibitors of DLL4
- •Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment
- •Known bleeding diathesis, esophageal varices, or angioplasty
- •Pulmonary hemorrhage or gross hemoptysis within 12 months
- •Known arterial or venous thrombosis or pulmonary embolism within 2 years
- •Concurrent use of systemic low molecular weight heparin or low dose warfarin
- •Presence of brain metastases
- •Cerebrovascular accident or transient ischemic attack within 2 years
- •Cardiovascular events, such as myocardial infarction, unstable/severe angina, coronary/peripheral artery bypass graft, unstable cardiac arrhythmia requiring medication, congestive heart failure (NYHA > class II), within 2 years
- •Tumors with squamous cell histology
- •Major surgical procedure within 90 days
- •Pregnancy or lactation
- •Known HIV positive or Hepatitis A, B, or C infection
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Echocardiogram Evaluations
时间窗: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.
Echocardiogram parameters included left ventricular ejection fraction (LVEF) and pulmonary arterial pressure (PAP). The TEAEs related to echocardiogram evaluations in participants were reported.
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: From the first dose of MEDI0639 until the end of participation in the study. Maximum time frame across participants was 4 years.
A serious AE (SAE) is any AE that results in death (refers to an event, which risk of death at the time of the event; it does not refer to an event that may have led to death), is immediately life threatening, require (or prolong) inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, or is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above. Treatment-emergent SAEs defined as SAEs present at baseline that worsened in intensity after administration of study drug or SAEs absent at baseline that emerged after administration of study drug. The SAEs were summarized using MedDRA version 18.1.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and Physical Examination
时间窗: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) were performed at baseline and throughout the study. The TEAEs related to vital signs in participants were reported.
Maximum Tolerated Dose (MTD) of MEDI0639
时间窗: From the first dose of MEDI0639 to 21 days after the first dose
The MTD evaluation was based on the dose-limiting toxicity (DLT) evaluable population. DLT is defined as any Grade 3 or higher treatment-related toxicity that occurred during the DLT evaluation period (defined as the time from the first dose of MEDI0639 to 21 days after the first dose), except for National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 hypertension that could be controlled within 96 hours; Grade 3 symptomatic hypertension of greater than (\>) 180 millimetre of mercury (mm Hg) systolic or \>120 mm Hg diastolic or asymptomatic hypertension of \>200 mm Hg systolic or \>120 mm Hg diastolic was considered a DLT.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: From the first dose of MEDI0639 until 90 days after the last dose of MEDI0639. Maximum time frame across participants was 11 months.
An adverse event (AE) is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. Treatment-emergent AEs (TEAEs) were events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug, for the period extending to 90 days after the last dose of study drug. The AEs were summarized using Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Laboratory Parameters
时间窗: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.
Laboratory evaluations of blood and urine samples were performed, including hematology (white blood cell \[WBC\] count with differential, red blood cell \[RBC\] count, hematocrit, hemoglobin, platelet count, mean corpuscular volume \[MCV\], and mean corpuscular hemoglobin concentration \[MCHC\]); serum chemistry (calcium, chloride, magnesium, potassium, sodium, bicarbonate, aspartate transaminase \[AST\], alanine transaminase \[ALT\], alkaline phosphatase, total bilirubin, liver function test, gamma glutamyl transferase \[GGT\], lactate dehydrogenase, uric acid, creatinine, blood urea nitrogen \[BUN\], glucose, albumin, total protein, triglycerides, cholesterol, and troponin); and routine urinalysis. The TEAEs related to laboratory evaluations in participants were reported.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Electrocardiogram (ECG) Evaluations
时间窗: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.
ECG parameters included QT interval and corrected QT (QTc) interval. Electrocardiogram (ECG) parameters were assessed at baseline as well as throughout the study. All 12-lead ECGs performed during the study were obtained in triplicate. The TEAEs related to ECG evaluations in participants were reported.
次要结局
- Overall Survival(From study entry through the end of the study. Maximum time frame across participants was 4 years.)
- Progression-free Survival (PFS)(From study entry through the end of the study. Maximum time frame across participants was 4 years.)
- Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) After Cycle 1 Treatment Administration of MEDI0639(Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1)
- Number of Participants Positive With Antidrug Antibodies (ADA) for MEDI0639(On Day 1 of Cycles 1, 2, 3, and every other cycle thereafter, end of treatment, 30 days, and 3 and 6 months after the last dose of MEDI0639. Maximum time frame across participants was 14 months.)
- Maximum Observed Concentration (Cmax) After Cycle 1 Treatment Administration of MEDI0639(Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1)
- Clearance (CL) After Cycle 1 Treatment Administration of MEDI0639(Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1)
- Half-life (t1/2) After Cycle 1 Treatment Administration of MEDI0639(Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1)
- Percentage of Participants With Best Overall Response(From study entry through the end of the study. Maximum time frame across participants was 4 years.)
- Percentage of Participants With Objective Response(From study entry through the end of the study. Maximum time frame across participants was 4 years.)
- Percentage of Participants With Disease Control(From study entry through the end of the study. Maximum time frame across participants was 4 years.)
- Time to Response(From study entry through the end of the study. Maximum time frame across participants was 4 years.)
- Duration of Response (DR)(From study entry through the end of the study. Maximum time frame across participants was 4 years.)