First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1046 in Subjects With Malignant Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Genmab
- 入组人数
- 429
- 试验地点
- 98
- 主要终点
- Dose Escalation: Number of Participants With Dose Limiting Toxicity (DLT)
研究概览
简要总结
The goal of this trial is to learn about the antibody acasunlimab (an antibody also known as GEN1046) when it is used alone and when it is used together with standard of care treatment (docetaxel) or another antibody cancer drug, pembrolizumab (with or without chemotherapy), for treatment of patients with certain types of cancer. All subjects will receive active drug; no one will receive placebo.
This trial has 2 parts. The purpose of the first part is to find out if acasunlimab at various doses is safe and to find out the best doses of acasunlimab to use. The purpose of the second part is to give acasunlimab to more subjects to see how well the doses of acasunlimab selected in the first part work against cancer when given alone and how well they work when given with pembrolizumab with or without chemotherapy.
Trial details include:
- The average trial duration for an individual subject will be about 74 weeks.
- The average treatment duration for an individual subject will be about 21 weeks.
- The visit frequency will be weekly at first and lessening over time until visits are only once every 3 weeks.
详细描述
The trial is an open-label, multi-center safety trial of acasunlimab (GEN1046). The trial consists of 2 consecutive parts: a first-in-human (FIH) dose escalation (phase 1) and an expansion (phase 2a). The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) has been determined.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •For Dose Escalation:
- •Have a histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable and for whom there is no available standard therapy
- •For Expansion:
- •Have histologically or cytological confirmed diagnosis of relapsed or refractory, advanced and/or metastatic NSCLC, EC, UC, TNBC, SCCHN, or cervical cancer who are not anymore candidates for standard therapy For separate expansion cohorts: metastatic NSCLC without prior systemic treatment regimens for metastatic disease.
- •For Both Dose Escalation and Expansion
- •Have measurable disease according to RECIST 1.1
- •Have Eastern Cooperative Oncology Group (ECOG) 0-1
- •Have an acceptable hematological status
- •Have acceptable liver function
- •Have an acceptable coagulation status
- •Have acceptable renal function
排除标准
- •Have uncontrolled intercurrent illness, including but not limited to:
- •Ongoing or active infection requiring intravenous treatment with anti-infective therapy, or any ongoing systemic inflammatory condition requiring further diagnostic work-up or management during screening.
- •Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris or cardiac arrhythmia
- •Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg, despite optimal medical management
- •Ongoing or recent evidence of autoimmune disease
- •History of irAEs that led to prior checkpoint treatment discontinuation
- •Prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade
- •History of chronic liver disease or evidence of hepatic cirrhosis
- •History of non-infectious pneumonitis that has required steroids or currently has pneumonitis
- •History of organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of acasunlimab
- •Serious, non-healing wound, skin ulcer (of any grade), or bone fracture
- •Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger than 6 months) or progressive brain metastases or stroke
- •Prior therapy:
- •Radiotherapy within 14 days prior to first dose of acasunlimab. Note: palliative radiotherapy will be allowed.
- •Treatment with an anti-cancer agent (within 28 days or after at least 5 half-lives of the drug, whichever is shorter), prior to acasunlimab administration. Accepted exceptions are bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab
- •Toxicities from previous anti-cancer therapies that have not adequately resolved
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Expansion
Acasunlimab will be administered as monotherapy or in combination with either docetaxel, pembrolizumab, or pembrolizumab + standard chemotherapy in separate expansion cohorts.
干预措施: Acasunlimab in combination with docetaxel (in a single expansion cohort) (Biological)
Dose Escalation
Acasunlimab will be administered as monotherapy.
干预措施: Acasunlimab (Biological)
Expansion
Acasunlimab will be administered as monotherapy or in combination with either docetaxel, pembrolizumab, or pembrolizumab + standard chemotherapy in separate expansion cohorts.
干预措施: Acasunlimab (Biological)
Expansion
Acasunlimab will be administered as monotherapy or in combination with either docetaxel, pembrolizumab, or pembrolizumab + standard chemotherapy in separate expansion cohorts.
干预措施: Acasunlimab in combination with pembrolizumab (in a separate expansion cohort) (Biological)
Expansion
Acasunlimab will be administered as monotherapy or in combination with either docetaxel, pembrolizumab, or pembrolizumab + standard chemotherapy in separate expansion cohorts.
干预措施: Acasunlimab in combination with pembrolizumab and standard chemotherapy (in separate expansion cohorts) (Biological)
结局指标
主要结局
Dose Escalation: Number of Participants With Dose Limiting Toxicity (DLT)
时间窗: During first cycle (21 days) for each cohort
Toxicities will be graded for severity according to Common Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0.
Dose Escalation and Monotherapy Expansion Cohorts: Number of Participants With Adverse Events (AEs)
时间窗: From first dose until the end of the study (up to 60 days after the last dose)
Dose Escalation and Monotherapy Expansion Cohorts: Number of Participants With Shifts From Baseline in Safety Laboratory Parameters
时间窗: From first dose until the end of the study (up to 60 days after the last dose)
Expansion Cohort 1: Objective Response Rate (ORR)
时间窗: Up to 3 years
ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on response evaluation criteria in solid tumours (RECIST).
Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLT)
时间窗: During first cycle (21 days)
In this trial, a DLT was defined as any grade 5 toxicity, grade 4 neutropenia lasting more than 7 days, grade 3 and 4 febrile neutropenia, grade 4 thrombocytopenia for minimal duration of 7 days, grade 3\&4 hemorrhage associated with thrombocytopenia of ≥ grade 3 requiring platelet transfusion, grade 4 anemia, liver toxicity (transaminases and bilirubin elevations), grade 3 nausea that didn't respond to optimal antiemetic treatment within 7 days, grade ≥3 vomiting that didn't respond to optimal antiemetic treatment within 3 days, grade ≥3 diarrhea that didn't respond to optimal antidiarrheal treatment within 3 days, grade 3 immune-related adverse event (irAEs) that didn't improve to ≤ grade 1 within 7 days by appropriate care or with corticosteroids (with exceptions per protocol), any grade 4 irAE, any other ≥ grade 3 non-hematological adverse events (AE), which occurred during the first GEN1046 treatment cycle (with exceptions per protocol).
Dose Escalation and Monotherapy Expansion Cohorts: Number of Participants With Treatment-emergent Adverse Events (AEs)
时间窗: Up to approximately 5 years, 10 months
An AE was defined as any untoward medical occurrence in a clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Treatment-emergent AEs were any AEs that developed or worsened after the first dose of a medicinal product. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Expansion Cohort 1: Objective Response Rate (ORR)
时间窗: Up to approximately 5 years, 10 months
ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on response evaluation criteria in solid tumors (RECIST v1.1). CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have had a reduction in short axis to \<10 millimeters (mm). PR was defined as ≥30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LDs.
次要结局
- Expansion Cohort 1: Number of Participants With AEs(From first dose until the end of the study (up to 60 days after the last dose))
- Expansion Cohort 1: Number of Participants With Shifts From Baseline in Safety Laboratory Parameters(From first dose until the end of the study (up to 60 days after the last dose))
- Combination Therapy Expansion Cohorts: Number of Participants With AEs(From first dose until the end of the study (up to 60 days after the last dose))
- Combination Therapy Expansion Cohorts: Number of Participants With Shifts From Baseline in Safety Laboratory Parameters(From first dose until the end of the study (up to 60 days after the last dose))
- All Parts: Total Body Clearance (CL) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Volume of Distribution (Vd) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Area Under the Concentration-Time Curve from Time Zero to Day 21 (AUC21days) of GEN1046(Predose and postdose at multiple timepoints for 21 days up to end of safety follow up (up to 60 days after last dose))
- All Parts: Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Area Under the Concentration-Time Curve from Time Zero to Last Quantifiable Concentration (AUClast) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Maximum Observed Plasma Concentration (Cmax) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Time to Reach Cmax (Tmax) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Elimination Half-life (t½) of GEN1046(Predose and postdose at multiple timepoints up to end of safety follow up (up to 60 days after last dose))
- All Parts: Number of Participants with Anti-drug Antibodies (ADAs)(Up to 3 years)
- Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: ORR(Up to 3 years)
- Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: Disease Control Rate (DCR)(Up to 3 years)
- All Parts: Duration of Response (DoR)(Up to 3 years)
- Expansion Cohort 1: Progression Free Survival (PFS)(Up to 3 years)
- Expansion Cohort 1: Overall survival (OS)(Up to 3 years)
- Combination Therapy Expansion Cohorts: Number of Participants With Treatment-emergent AEs(Up to approximately 5 years, 10 months)
- Dose Escalation: Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) of GEN1046(Cycle 1 and Cycle 2 (cycles were 21 days))
- Dose Escalation: Maximum Observed Plasma Concentration (Cmax) of GEN1046(Cycle 1 and Cycle 2 (cycles were 21 days))
- Number of Participants With Anti-drug Antibodies (ADAs) to GEN1046(Up to approximately 5 years, 10 months)
- Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: ORR(Up to approximately 5 years, 10 months)
- Dose Escalation and Expansion Cohorts 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13: Disease Control Rate (DCR)(Up to approximately 5 years, 10 months)
- Duration of Response (DoR)(Up to approximately 5 years, 10 months)
- Expansion Cohort 1: Progression Free Survival (PFS)(Up to approximately 5 years, 10 months)
- Expansion Cohort 1: Overall Survival (OS)(Up to approximately 5 years, 10 months)