An Open-Label, Multicenter, Randomized, Dose-Escalation and Extension, Phase IA/IB Study to Evaluate Safety and Anti-Tumor Activity of RO7284755, A PD-1 Targeted IL-2 Variant (IL-2V) Immunocytokine, Alone or in Combination With Atezolizumab in Participants With Advanced and/or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 189
- 试验地点
- 24
- 主要终点
- Percentage of Participants with Adverse Events in Part 1 and Part 2
研究概览
简要总结
This is an entry-into-human study and will assess the effects of eciskafusp alfa (RO7284755) as a single agent and in combination with atezolizumab in adult participants with solid tumors considered responsive to checkpoint inhibition blockade. The maximum duration in the study for each participant will be up to 28 months.
详细描述
The study consists of three parts: dose-escalation of eciskafusp alfa as a single agent (Part 1), dose-escalation of eciskafusp alfa in combination with atezolizumab (Part 2), and extension of eciskafusp alfa as a single agent and/or in combination with atezolizumab (Part 3).
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Locally advanced/unresectable or metastatic disease
- •No standard of care (SoC) (approved) treatments are available for the participant, or the participant cannot tolerate such treatments
- •Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
- •Eastern Cooperative Oncology Group Performance Status 0 to 1
- •Life expectancy of >=12 weeks
- •Consent to provide an archival tumor tissue sample
- •Adequate cardiovascular, hematological, coagulative, hepatic and renal function
排除标准
- •Rapid disease progression or suspected hyperprogression or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention
- •Untreated central nervous system (CNS) metastases
- •Treated asymptomatic CNS metastases
- •Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >= 2 weeks before Cycle1 Day 1 (C1D1)
- •Active or history of carcinomatous meningitis/leptomeningeal disease
- •Uncontrolled tumor-related pain or symptomatic hypercalcemia
- •Concurrent second malignancy
- •Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results
- •Episode of significant cardiovascular/cerebrovascular acute disease within 28 days before study treatment administration
- •Active or uncontrolled infections
- •Known HIV infection
- •Hepatitis B virus (HBV) or hepatitis C virus infection
- •Adverse events related to any prior radiotherapy, chemotherapy, targeted therapy, CPI therapy or surgical procedure must have resolved to Grade <=1, except alopecia Grade 2 peripheral neuropathy, and hypothyroidism and/or hypopituitarism on a stable dosage of hormone replacement therapy
- •Participants with bilateral pleural effusion
- •Major surgery or significant traumatic injury < 28 days before study treatment administration or anticipation of the need for major surgery during study treatment
- •Known allergy or hypersensitivity to any component of the formulations of the IMPs to be administered, including but not limited to hypersensitivity to Chinese hamster ovary cell products or other recombinant or humanized antibodies
- •History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
- •Previous treatment with Interleukin-2 (IL-2)/Interleukin-5 (IL-15)-like cytokines. IL-2/IL-15 use as an adjunct treatment component for adoptive cell therapy is permitted. In Part 3, patients who have received adoptive cell therapy such as tumor-infiltrating lymphocytes (TIL) are excluded.
研究组 & 干预措施
Eciskafusp Alfa as a Single Agent
Part 1: Dose-escalation of eciskafusp alfa as a single agent. eciskafusp alfa will be either an intravenous administration (IV) or subcutaneous administration (SC) in multiple-ascending doses.
干预措施: Eciskafusp Alfa (Drug)
Eciskafusp Alfa in Combination with Atezolizumab
Part 2: Dose-escalation of eciskafusp alfa in combination with atezolizumab.
干预措施: Eciskafusp Alfa (Drug)
Eciskafusp Alfa as a Single Agent and/or with Atezolizumab
Part 3: Extension of eciskafusp alfa as a single agent and/or in combination with atezolizumab.
干预措施: Eciskafusp Alfa (Drug)
Eciskafusp Alfa in Combination with Atezolizumab
Part 2: Dose-escalation of eciskafusp alfa in combination with atezolizumab.
干预措施: Atezolizumab (Drug)
Eciskafusp Alfa as a Single Agent and/or with Atezolizumab
Part 3: Extension of eciskafusp alfa as a single agent and/or in combination with atezolizumab.
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Percentage of Participants with Adverse Events in Part 1 and Part 2
时间窗: From randomization until end of Part 1 and Part 2 (up to approximately 1.5 months)
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. All AE events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Percentage of Participants with Dose-Limiting Toxicities in Part 1 and Part 2
时间窗: From randomization up to day 14 (Part 1) or day 28 (Part 2)
A DLT is defined as a clinically significant AE (classified according to the NCI CTCAE version 5) or significant laboratory abnormality that occur during the DLT assessment periods, during Part 1 and Part 2 only, and is considered by the Investigator to be related to eciskafusp alfa or to the combination of eciskafusp alfa and atezolizumab. In Part 2, expected toxicities that are, in the opinion of the Investigator, entirely attributable to atezolizumab, will not be considered DLTs.
Investigator Assessed Objective Response Rate according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in Part 3
时间窗: From start of extension phase until disease progression, drug discontinuation, withdrawal or death (up to approximately 26 months)
Objective response rate (ORR) was defined as the percentage of participants with investigator-assessed objective response of complete response (CR) or partial response (PR). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions).
Recommended Dose for Extension (RDE) of Eciskafusp Alfa in Parts 1 and 2
时间窗: From randomization up to day 14 (Part 1) or day 28 (Part 2)
次要结局
- Investigator Assessed Objective Response Rate according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in Parts 1 and 2(From randomization until end of Part 1 and Part 2 (up to approximately 1.5 months))
- Percentage of Participants with Adverse Events in Part 3(From start of extension phase until disease progression, drug discontinuation, withdrawal or death (up to approximately 26 months))
- Duration of Response in Part 3(From start of extension phase until disease progression, drug discontinuation, withdrawal or death (up to approximately 26 months))
- Percentage of Immune and Tumor Cells with Positive Programmed Cell Death-1 (PD-1) and Programmed Cell Death-Ligand 1 (PD-L1) Expression in the Tumor Microenvironment (TME)(Baseline)
- Change from Baseline in Percentage of Immune Cell Subsets(Baseline to End of Treatment (up to approximately 28 months))
- Disease Control Rate in Part 3(From start of extension phase until disease progression, drug discontinuation, withdrawal or death (up to approximately 26 months))
- Minimum Concentration (Cmin) for Eciskafusp Alfa(Predose, C1 Days 1, 2, 3, 5, 8, 9, 10, 12, 15, 16, 17, and 19; C2 Days 1, 2, 8, 9, 10, 12, 15, and 16; C3 Days 1, 2, 3, and 8; C4 Days 1 and 2; C5 Days1, 2, and 8; and days 1 and 2 for any subsequent cycles (Up to 28 months))
- Maximum Concentration (Cmax) for Eciskafusp Alfa(Predose, C1 Days 1, 2, 3, 5, 8, 9, 10, 12, 15, 16, 17, and 19; C2 Days 1, 2, 8, 9, 10, 12, 15, and 16; C3 Days 1, 2, 3, and 8; C4 Days 1 and 2; C5 Days1, 2, and 8; and days 1 and 2 for any subsequent cycles (Up to 28 months))
- Progression-free survival (PFS) in Part 3(From start of extension phase until disease progression, drug discontinuation, withdrawal or death (up to approximately 26 months))
- Change from Baseline in Antidrug Antibody (ADA) to Eciskafusp Alfa(Up to 28 months)
- Volume of Distribution at Steady-State Conditions (Vss) for Eciskafusp Alfa(Predose, C1 Days 1, 2, 3, 5, 8, 9, 10, 12, 15, 16, 17, and 19; C2 Days 1, 2, 8, 9, 10, 12, 15, and 16; C3 Days 1, 2, 3, and 8; C4 Days 1 and 2; C5 Days1, 2, and 8; and days 1 and 2 for any subsequent cycles (Up to 28 months))
- Percentage of Partcipants with ADAs to Eciskafusp Alfa(Up to 28 months)
- Area Under the Curve (AUC) for Eciskafusp Alfa(Predose, C1 Days 1, 2, 3, 5, 8, 9, 10, 12, 15, 16, 17, and 19; C2 Days 1, 2, 8, 9, 10, 12, 15, and 16; C3 Days 1, 2, 3, and 8; C4 Days 1 and 2; C5 Days1, 2, and 8; and days 1 and 2 for any subsequent cycles (Up to 28 months))
- Clearance (CL) for Eciskafusp Alfa(Predose, C1 Days 1, 2, 3, 5, 8, 9, 10, 12, 15, 16, 17, and 19; C2 Days 1, 2, 8, 9, 10, 12, 15, and 16; C3 Days 1, 2, 3, and 8; C4 Days 1 and 2; C5 Days1, 2, and 8; and days 1 and 2 for any subsequent cycles (Up to 28 months))
- Change from Baseline in Percentage of Immune Markers(Baseline to End of Treatment (up to approximately 28 months))
- Percentage of Immune Cells with CD8+ PD1+ and CD8+ PD1+ TCF7+ Expression(Baseline)
- Blood Tumor Mutational Burden(Baseline)