Phase I, First-in-Human, Open-Label, Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M6223, an Inhibitor of TIGIT, as Single Agent and in Combination With Bintrafusp Alfa (Anti-PDL1/ TGFß Trap) in Participants With Metastatic or Locally Advanced Solid Unresectable Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 58
- 试验地点
- 7
- 主要终点
- Part IA and IB: Occurrence of Treatment-Emergent Adverse Events (TEAEs) as per Severity and Deaths
研究概览
简要总结
The main purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), immunogenicity and (if observed) the maximum tolerated dose (MTD) of M6223 as a single agent (Part 1A) for both the every 2 weeks (Q2W) regimen and the every 3 weeks (Q3W) regimen and of M6223 combined with bintrafusp alfa (Part 1B) for Q2W regimen in participants with metastatic or locally advanced solid unresectable tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Participants have histologically or cytologically proven locally advanced or advanced solid malignancies who are refractory to or have progressed under standard treatment and have no other treatment options known to confer clinical benefit
- •Participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening
- •Participant has a formalin-fixed paraffin-embedded block containing tumor tissue or a minimum of 15 (preferably 25) unstained tumor slides suitable for immunohistochemistry-based staining of protein expression
- •Participants with life expectancy of at least 12 weeks
- •Participants with measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
- •Adequate hematological, hepatic and renal function as defined in the protocol
- •Other protocol defined inclusion criteria may apply
排除标准
- •Participants with persisting toxicity related to prior therapy Grade greater than (>) 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, however, alopecia, sensory neuropathy Grade less than or equal to (<=) 2, or other non-immune-related Grade <= 2 not constituting a safety risk
- •Participants with prior organ transplantation including allogeneic stem cell transplantation
- •Participants with prior toxicity related to an immune checkpoint inhibitor Grade greater than equal to (>=) 3 NCI-CTCAE Version 5.0 unless resolved to Grade <= 1 prior to study inclusion
- •Participants with current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of > 450 milli seconds (ms) on triplicate 12-lead ECG or impaired cardiovascular function, ventricular tachycardia, hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome
- •A history of vascular, cardiovascular or cerebrovascular disease like, cerebral vascular accident/stroke (less than [<] 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), deep vein thrombosis (< 3 months prior to enrollment) or pulmonary thrombosis/embolism (< 3 months prior to enrollment)
- •Other protocol defined exclusion criteria may apply
研究组 & 干预措施
Part 1A: M6223 Monotherapy
干预措施: M6223 (Drug)
Part1B: M6223 + Bintrafusp alfa
干预措施: M6223 (Drug)
Part1B: M6223 + Bintrafusp alfa
干预措施: Bintrafusp alfa (Drug)
结局指标
主要结局
Part IA and IB: Occurrence of Treatment-Emergent Adverse Events (TEAEs) as per Severity and Deaths
时间窗: Time from first study drug administration to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years)
Part IA and IB: Occurrence of Treatment-Emergent Adverse Events (TEAEs) and Treatment Related Adverse Events (TRAEs) According to the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) version 5
时间窗: Time from first study drug administration to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years)
Part IA and IB: Occurrence of Clinically Significant Change From Baseline in Clinical Laboratory Measures
时间窗: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years)
Part IA and IB: Occurrence of Clinically Significant Change From Baseline in Electrocardiogram Findings
时间窗: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years)
Part IA and IB: Occurrence of Clinically Significant Change From Baseline in Vital Signs
时间窗: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years)
Part IA and IB: Occurrence of Change From Baseline in Eastern Cooperative Oncology Group Performance Status
时间窗: Time from baseline to final assessment at end of safety follow-up visit (up to a maximum of approximately 2 years)
Part 1A and 1B: Occurrence of Dose Limiting Toxicities (DLTs) During the DLT Observation Period (28 Days)
时间窗: Day 1 to Day 28
Part 1A and 1B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
时间窗: Day 1 to Day 28
A DLT is defined as any Grade ≥ 3 non-hematologic AE or any Grade ≥ 4 hematologic AE according to the NCI-CTCAE, occurring during the DLT observation period (28 days from first administration of study intervention) that is not clearly related to the underlying disease or any previous or concomitant medication, concomitant disease or unrelated illness. A DLT must be confirmed by the Safety Monitoring Committee. DLT is considered if the following related AEs occur: • Grade ≥ 3 neutropenia with clinical signs/symptoms (e.g., febrile neutropenia). • Grade ≥ 3 thrombocytopenia with medically concerning bleeding. • A study intervention-related treatment-emergent AE that in the opinion of the SMC is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. • Grade ≥ 3 hematological AE with symptoms that require growth factor support or transfusion to prevent further damage to the participant.
Part 1A and 1B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
时间窗: Approximately 2 years 11 months
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE 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. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.
Part 1A and 1B: Number of Participants With TEAES With Severity of Grade Greater or Equal to 3 and TEAEs Leading to Deaths
时间窗: Approximately 2 years 11 months
An adverse event (AE) is any untoward medical occurrence in a participant temporally associated with the use of the study intervention, regardless of causality. A serious AE results in death, is life-threatening, requires/prolongs hospitalization, causes disability/incapacity, leads to a congenital anomaly/birth defect, or is otherwise medically significant. Treatment-emergent adverse events (TEAEs) are those that begin or worsen after the first dose through 30 days post-treatment, and include both serious and non-serious events. Treatment-related TEAEs are those reasonably related to the study intervention. Severity is graded per CTCAE v24.1: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe/medically significant), Grade 4 (life-threatening/disabling), Grade 5 (death related to AE).
Part 1A and 1B: Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values
时间窗: Approximately 2 years 11 months
Number of participants with clinically meaningful change from baseline in laboratory parameters were reported. Clinically meaningful abnormalities (identified as laboratory values having CTCAE grades \>= 3). Laboratory investigation included hematology, biochemistry, urinalysis, and coagulation.
Part 1A and 1B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
时间窗: Approximately 2 years 11 months
Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.
Part 1A and 1B: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs
时间窗: Approximately 2 years 11 months
Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Relevance was decided by the investigator. Number of participants with clinically relevant change from baseline in vital signs were reported. Clinical relevance was defined as increase more than equal to (\>=) 3° temperature, \>40 beats heart rate increase, \>40 mmHG increase in systolic or diastolic blood pressure, \>10 breaths in respiratory rate increase.
Part 1A and 1B: Number of Participants With Worsened Post Baseline Shift in Eastern Cooperative Oncology Group Performance Status
时间窗: Approximately 2 years 11 months
The number of participants who experienced worse post baseline shift were assessed as per ECOG performance status score recorded during the treatment. The ECOG score is categorized as Grade 0, 1, 2, 3 and 4 where Grade 0=fully active, Grade 1=restricted in physically strenuous activity, Grade 2=unable to carry out any work activities, Grade 3=capable of only limited self-care and Grade 4=completely disabled.
次要结局
- Part IA and 1B: Immunogenicity of M6223 Measured by Antidrug Antibody (ADA) Assays(Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) up to end of safety follow-up visit (up to a maximum of 2 years))
- Part 1A and Part 1B: Area Under Serum Concentration-Time Curve Over a Dosing Interval From Time Zero to Tau (τ) (AUCτ) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1B: Maximum Observed Serum Concentration (Cmax) of Bintrafusp alfa(Pre-dose up to 14 days (in Q2W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen))
- Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Bintrafusp alfa(Pre-dose up to 14 days (in Q2W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen))
- Part 1A and Part 1B: Time to Reach Maximum Serum Concentration (Tmax) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Apparent Terminal Half-Life (t1/2) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1B: Immunogenicity of Bintrafusp alfa Measured by Antidrug Antibody (ADA) Assays(Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen) up to end of safety follow-up visit (up to a maximum of 2 years))
- Part 1A and IB: Best Overall Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years))
- Part 1A and 1B: Change from Baseline in QT Interval(From Day 1 Cycle 1 (Baseline) up to Day 1 Cycle 7 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen))
- Part 1A and 1B: Disease Control According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years))
- Part 1A and 1B: Overall Survival(Time from first treatment to end of study (planned 12 months after last patient started treatment))
- Part 1A and 1B: Progression-free Survival Time According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years))
- Part 1A and 1B: Duration of Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years))
- Part 1A and 1B: Time to Tumor Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first, (approximately assessed up to 2 years))
- Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Maximum Observed Serum Concentration (Cmax) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Elimination Rate Constant (Lambda z) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Area Under Serum Concentration-Time Curve Over a Dosing Interval From Time Zero to Tau (AUC-tau) of M6223(Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycle 1 (Cycle is of 21 days in Q3W regimen))
- Part 1A and Part 1B: Time to Reach Maximum Serum Concentration (Tmax) of M6223(Cycle 1 and 2: Day 1 (-2h, EOI, 4-6h), Day 2 (25-31h), Day 5 (±1h), Day 8 (±1h); Cycle 3 to end of treatment: Day 1 (-2h pre-dose only))
- Part 1A and Part 1B: Apparent Terminal Half-Life (t1/2) of M6223(Cycle 1 and 2: Day 1 (-2h, EOI, 4-6h), Day 2 (25-31h), Day 5 (±1h), Day 8 (±1h); Cycle 3 to end of treatment: Day 1 (-2h pre-dose only))
- Part 1B: Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa(Day 1 of Treatment of Cycles 1 and 4 from time zero to 14 days postdose)
- Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Bintrafusp Alfa(Day 1 of Treatment of Cycles 1 and 4 from time zero to 14 days postdose)
- Part IA and 1B: Number of Participants With Positive Antidrug Antibody (ADA) Assays(Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) up to end of safety follow-up visit ( approximately 2 years 11 months))
- Part 1A and IB: Best Overall Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months))
- Part 1A and 1B: Duration of Response (DOR) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first( approximately 2 years 11 months))
- Part 1A and 1B: Time to Tumor Response (TTR) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months)))
- Part 1A and 1B: Disease Control According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months)))
- Part 1A and 1B: Progression-free Survival Time According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator(From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months))
- Part 1A and 1B: Overall Survival(From first study drug administration to the date of death due to any cause (approximately 2 years 11 months))