A Phase 1 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI9447 Alone and in Combination With MEDI4736 in Adult Subjects With Select Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 192
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs) in Dose-escalation Phase
研究概览
简要总结
The purpose of this study is to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI9447 Alone and in Combination with MEDI4736 in Adult Participants with Select 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 101 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult participants; age ≥ 18
- •Written and signed informed consent must be obtained
- •Have histologic or cytologic documentation of solid tumor including EGFRm NSCLC
- •Participants must have at least 1 lesion that is measurable using RECIST guidelines
- •Participants must consent to provide archived tumor specimens or tumor biopsies for correlative biomarker studies.
- •Eastern Cooperative Oncology Group performance score of 0 or 1
- •Adequate organ function
排除标准
- •Prior treatment with tumor necrosis factor receptor superfamily agonists including OX40, CD27, CD137 (4-1BB), CD357 (GITR). One cohort also excludes anti CTLA-4, PD-L1, and anti PD-L
- •Participants who have received prior therapy with regimens containing CTLA-4, PD-L1, or PD-1 antagonists may be permitted to enroll under certain conditions
- •Cardiac or peripheral vascular disease meeting any of the following criteria:
- •Past history of myocardial infarction in the prior 12 months
- •Past history of stroke or transient ischemic attack requiring medical therapy
- •Congestive heart failure ≥ Class 3 based on New York Heart Association Functional Classification
- •Grade 3 or greater edema (eg, peripheral, pulmonary)
- •History of Grade 3 or greater thromboembolic events in the prior 12 months
- •Participants with active tuberculosis are ineligible. In settings where there is clinical or radiographic evidence of tuberculosis, active disease must be ruled out
- •Active or prior documented autoimmune or inflammatory disorders
- •Untreated central nervous system (CNS) metastatic disease
- •Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C
- •Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, ductal carcinoma in situ of the breast that has been surgically cured
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, uncontrolled hypertension, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirement
研究组 & 干预措施
Dose-escalation: Oleclumab Dose 2 + Durvalumab Dose 1
Participants will receive oleclumab Dose 2 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: Oleclumab Dose 1
Participants will receive oleclumab Dose 1 intravenously (IV) every two weeks (Q2W) until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: Oleclumab Dose 2
Participants will receive oleclumab Dose 2 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: Oleclumab Dose 3
Participants will receive oleclumab Dose 3 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: Oleclumab Dose 4
Participants will receive oleclumab Dose 4 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: Oleclumab Dose 1 + Durvalumab Dose 1
Participants will receive oleclumab Dose 1 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: Oleclumab Dose 1 + Durvalumab Dose 1
Participants will receive oleclumab Dose 1 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
Dose-escalation: Oleclumab Dose 2 + Durvalumab Dose 1
Participants will receive oleclumab Dose 2 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
Dose-escalation: OleclumabDose 3 + Durvalumab Dose 1
Participants will receive oleclumab Dose 3 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: OleclumabDose 3 + Durvalumab Dose 1
Participants will receive oleclumab Dose 3 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
Dose-escalation: OleclumabDose 4 + Durvalumab Dose 1
Participants will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-escalation: OleclumabDose 4 + Durvalumab Dose 1
Participants will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
Dose-expansion (CRC): Oleclumab Dose 4 + Durvalumab Dose 1
Participants with previously treated microsatellite stable-colorectal cancer (MSS-CRC) will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-expansion (CRC): Oleclumab Dose 4 + Durvalumab Dose 1
Participants with previously treated microsatellite stable-colorectal cancer (MSS-CRC) will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
Dose-expansion (Pancreatic adenocarcinoma): Oleclumab Dose 4+ Durvalumab Dose 1
Participants with previously treated pancreatic adenocarcinoma will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-expansion (Pancreatic adenocarcinoma): Oleclumab Dose 4+ Durvalumab Dose 1
Participants with previously treated pancreatic adenocarcinoma will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
Dose-expansion (NSCLC): Oleclumab Dose 4 + Durvalumab Dose 1
Participants with previously treated EGFRm NSCLC will receive oleclumab Dose 4 IV followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Oleclumab (Drug)
Dose-expansion (NSCLC): Oleclumab Dose 4 + Durvalumab Dose 1
Participants with previously treated EGFRm NSCLC will receive oleclumab Dose 4 IV followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first.
干预措施: Durvalumab (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs) in Dose-escalation Phase
时间窗: From Day 1 to Day 28 after first dose of study drug
A DLT was defined as any Grade 3 or higher treatment-related toxicity that occurred during the DLT-evaluation period, which included any Grade 4 immune-mediated adverse event (imAE), any \>= Grade 3 colitis, any Grade 3 or 4 non-infectious pneumonitis irrespective of duration, any Grade 3 imAE (excluding colitis or pneumonitis, did not downgrade to \<= Grade 2 within 3 days after onset of the event despite maximal medical supportive care including systemic corticosteroids or did not downgrade to \<= Grade 1 or baseline within 14 days), liver transaminase elevation \>= 5 × but \<= 8 × upper limit of normal (ULN) that did not downgrade to Grade 2 within 5 days after onset with optimal medical management (including systemic corticosteroids), transaminase elevation \> 8 × ULN or total bilirubin (TBL) \> 5 × ULN regardless of duration or reversibility, or any increase in aspartate aminotransferase or alanine aminotransferase \> 3 × ULN and concurrent increase in TBL \> 2 × ULN (Hy's Law).
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
时间窗: From Day 1 through 200.1 weeks (corresponding to maximum observed duration)
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as 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.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
时间窗: From Day 1 through 200.1 weeks (corresponding to maximum observed duration)
Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, thyroid function tests, coagulation, and urinalysis.
Number of Participants With Abnormal Vital Signs Reported as TEAEs
时间窗: From Day 1 through 188.1 weeks (corresponding to maximum observed duration)
Participants with abnormal vital signs (temperature, blood pressure, pulse rate, and respiratory rate) reported as TEAEs are reported.
Number of Participants With Change From Baseline in QTcF
时间窗: Baseline (prior to Day 1 dose) through 188.1 weeks (corresponding to maximum observed duration)
Number of participants with change from Baseline in QTcF (\> 60 msec and \> 90 msec) is reported.
次要结局
- Overall Survival (OS)(Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration))
- Maximum Observed Serum Concentration (Cmax) of MEDI9447(Day 1 (pre-dose, and 10 minutes and 2 hours post end of infusion), Day 57 (pre-dose and 10 minutes post end of infusion))
- Area Under the Serum Concentration Time Curve From 0 To 14 Days Post First Dose [AUC(0-14)] of MEDI9447(Day 1 (pre-dose; 10 minutes and 2 hours post end of infusion))
- Time To Maximum Observed Serum Concentration (Tmax) of MEDI9447(Day 1 (pre-dose; 10 minutes, 2 hours post end of infusion); Day 57 (pre-dose; 10 minutes post end of infusion))
- Percentage of Participants With Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1(Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration))
- Percentage pf Participants With Disease Control (DC) per RECIST v1.1(Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration))
- Duration of Response (DoR) per RECIST v1.1(Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration))
- Progression-Free Survival (PFS)(Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration))
- Observed Lowest Serum Concentration Reached Before the Next Dose (Ctrough) of MEDI9447(Day 1 (pre-dose; 10 minutes, 2 hours post end of infusion); Day 57 (pre-dose; 10 minutes post end of infusion))
- Accumulation Ratio for Cmax (Rac Cmax) of MEDI9447(Day 57 (pre-dose; 10 minutes post end of infusion))
- Accumulation Ratio for Ctrough (Rac Ctrough) of MEDI9447(Day 57 (pre-dose; 10 minutes post end of infusion))
- Cmax of MEDI4736(Day 1 (prior to start of MEDI9447 infusion and 10 minutes post end of MEDI4736 infusion))
- Tmax of MEDI4736(Day 1 (prior to start of MEDI9447 infusion and 10 minutes post end of MEDI4736 infusion))
- Ctrough of MEDI4736(Day 1 (prior to start of MEDI9447 infusion and 10 minutes post end of MEDI4736 infusion), Day 57 (prior to start of MEDI9447 infusion))
- Rac Ctrough of MEDI4736(Day 57 (prior to start of MEDI4736 infusion))
- Number of Participants With Positive Anti-Drug Antibody Response (ADA) to MEDI9447(Day 1 through 192.3 weeks (Days 1 , 29, and 57, EOT, and 30 days post end of treatment))
- Number of Participants With Positive ADA to MEDI4736(Day 1 through 200.1 weeks (Day 1 through 192.3 weeks (Days 1 , 29, and 57, EOT, and 30 days post end of treatment))