A Phase 1b/2, Open-label Study to Evaluate the Safety and Tolerability of MEDI6469 in Combination With Immune Therapeutic Agents or Therapeutic Monoclonal Antibodies in Subjects With Selected Advanced Solid Tumors or Aggressive B-cell Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 48
- 试验地点
- 14
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)
研究概览
简要总结
The main purpose of this study is to determine the best dose of MEDI6469 that is safe and tolerable when given as monotherapy and in combination with tremelimumab, MEDI4736 (durvalumab), or rituximab in participants with either advanced solid tumors or diffuse large B-cell lymphoma (DLBCL). Tremelimumab and MEDI4736 (durvalumab) will be tested with MEDI6469 in a set of participants with advanced solid tumors while rituximab will be tested with MEDI6469 in participants with DLBCL. MEDI6469 will be tested as monotherapy in participants with advanced solid tumors.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults >/= 18 years old
- •Histologically or cytologically confirmed advanced solid tumors that are refractory to standard therapy or for which no standard therapy exists (Monotherapy and in Cohorts A and B)
- •At least one lesion measurable by RECIST not previously irradiated (Monotherapy and in Cohorts A and B)
- •Histologically confirmed DLBCL(Cohort C)
- •Adequate organ and marrow function
- •ECOG performance status of 0 or 1
- •Willingness to provide consent for biopsy samples
排除标准
- •Prior exposure to immunotherapy (either as a single agent or in combination) including but not limited to CD137 or OX40 agonists, anti-CTLA-4, anti-PD-1, or anti-PD-L1, anti-PD-L2 antibody or pathway-targeting agents
- •History of organ transplant that requires use of immunosuppressives
- •History of primary immunodeficiency or tuberculosis
- •Active or prior documented autoimmune disease within the past 3 years
- •Active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months
- •Major surgical procedure within 30 days prior to the first dose of investigational product or still recovering from prior surgery
- •Women who are pregnant or lactating
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year)
An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. TEAEs were events present at baseline that worsened in intensity after administration of study treatment or events absent at baseline that emerged after administration of study treatment.
Maximum Tolerated Dose (MTD) of MEDI6469
时间窗: From the first dose of study treatment through 28 days after the first dose (up to 28 days)
The MTD was the highest dose within a cohort where no more than 1 out of 6 participants experienced dose-limiting toxicities (DLTs) or the highest protocol-defined dose for each agent in the absence of exceeding the MTD.
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs
时间窗: From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year)
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, creatinine, sodium, blood urea nitrogen \[BUN\], bicarbonate, glucose, aspartate transaminase \[AST\], total bilirubin, C-reactive protein, gamma-glutamyl transpeptidase \[GGT\], lactate dehydrogenase, uric acid, potassium, alanine transaminase \[ALT\], alkaline phosphatase, albumin, total protein, triglycerides, and cholesterol); urinalysis; and coagulation parameters.
Number of Participants With Vital Signs and Physical Examination Abnormalities Reported as TEAEs
时间窗: From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year)
Vital signs examination included assessment of temperature, blood pressure, pulse rate, and respiratory rate. Physical examination included assessments of head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, psychiatric, dermatological, hematologic/lymphatic, and endocrine systems. The TEAEs related to these vital sign and physical examination abnormalities were reported.
Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as TEAEs
时间窗: From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year)
Electrocardiogram (ECG) parameters included atrial rate, PR interval, QRS duration, QTC interval, QT interval, and ventricular rate. All 12-lead ECGs performed during the study were obtained in triplicate. The TEAEs related to these ECG evaluation abnormalities were reported.
Number of Participants With DLTs
时间窗: From the first dose of study treatment through 28 days after the first dose (up to 28 days)
The DLT was any Grade 3 or higher treatment-related toxicity (including liver transaminase elevation higher than 8×upper limit of normal \[ULN\] or total bilirubin higher than 5×ULN; any \>=Grade 2 pneumonitis that did not resolve to \<=Grade 1 within 3 days) that occurred during the DLT time frame, and excluded the following: Grade 3 fatigue for less than or equal to (\<=) 7 days; Grade 3 endocrinopathy that was managed and the participant was asymptomatic; Grade 3 inflammatory reaction attributed to a local antitumor response that resolved to \<=Grade 1 within 30 days; concurrent vitiligo or alopecia of any grade; Grade 3 infusion-related reaction that resolved within 6 hours; and any more than or equal to (\>=) Grade 3 lymphopenia (unless clinically significant).
Number of Participants With Treatment-emergent Serious Adverse Events
时间窗: From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year)
A serious adverse event (SAE) was any AE that resulted in death, immediately life threatening, required (or prolonged) inpatient (or existing) hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly or birth defect in offspring of the participant, or an important medical event that could jeopardize the participant or required medical intervention to prevent one of the outcomes listed above. Treatment-emergent SAEs were defined as SAEs present at baseline that worsened in intensity after administration of study treatment or SAEs absent at baseline that emerged after administration of study treatment.
次要结局
- Disease Control Rate(From study entry until early termination (up to 1 year))
- Duration of Response (DOR)(From Study entry until early termination (up to 1 year))
- Maximum Observed Serum Concentration (Cmax)(MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment)
- Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf)(MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment.)
- Best Overall Response (BOR)(From study entry until early termination (up to 1 year))
- Systemic Clearance (CL)(MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment.)
- Objective Response Rate (ORR)(From study entry until early termination (up to 1 year))
- Progression-free Survival (PFS)(From Study entry until early termination (up to 1 year))
- Overall Survival (OS)(From Study entry until early termination (up to 1 year))
- Terminal Phase Elimination Half-Life (T1/2)(MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment.)
- Number of Participants Positive for Human Anti-mouse Antibodies (HAMA)(All treatment arms: Days 8, 15, 29, and end of treatment (up to 1 year). Additionally for MEDI6469 + rituximab arm: Days 3, 31, 59, and every 28 days thereafter until end of treatment (up to 1 year))