A Phase I, Open-label, Multi-center Dose Escalation Study of FAZ053 as Single Agent and in Combination With PDR001 in Adult Patients With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 154
- 试验地点
- 3
- 主要终点
- Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The purpose of this "first-in-human" study of FAZ053 is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of FAZ053 administered Intravenously (i.v.)as a single agent or in combination with PDR001 in adult patients with advanced solid tumors.
By blocking the interaction between Programmed Death Ligand-1 (PD-L1) and its receptors, Programmed Death-1 (PD-1) and B7.1, FAZ053 inhibits the PD-L1 immune checkpoint, resulting in activation of an antitumor immune response by activating effector T-cells and inhibiting regulatory T-cells.
This study has been designed as a Phase I, open-label, multi-center study with a dose escalation part of FAZ053 as single agent and in combination with PDR001, followed by a dose expansion part of FAZ053 as single agent.
FAZ053 will initially be dosed every three weeks. A less frequent dosing regimen such as every 6 weeks may be evaluated in parallel.
A patient may continue treatment with FAZ053 single agent or in combination with PDR001 until the patient experiences unacceptable toxicity, confirmed disease progression per immune related Response Criteria and/or treatment is discontinued at the discretion of the investigator or the patient.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent prior to any procedure.
- •Dose escalation cohorts of FAZ053 single agent and FAZ053 in combination with PDR001: Patients with advanced/metastatic solid tumors with measurable or non-measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 who may or may not have received prior treatment with an immune checkpoint inhibitor, who have progressed despite standard therapy, or for whom no standard therapy is available.
- •Dose expansion groups of FAZ053 single agent: Patients with advanced/metastatic solid tumors with at least one measurable lesion as determined by RECIST version 1.1 who may or may not have received prior treatment with an immune checkpoint inhibitor (for FAZ053 single agent no treatment with an anti-PD-L1 inhibitor is permitted), who have progressed despite standard therapy, or for whom no standard therapy is available and fit into one of the following groups:
- •FAZ053 single agent: TNBC/ Chordoma/ ASPS
- •Performance Status (PS) ≤ 2:
- •Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening/ baseline and during therapy on this study.
排除标准
- •Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local CNS-directed therapy (e.g. radiotherapy or surgery) or increasing doses of corticosteroids within the prior 2 weeks. Patients with treated brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study enrollment) and off of steroids for at least 2 weeks before administration of any study treatment.
- •History of severe hypersensitivity to study treatment excipients and additives or other monoclonal antibodies (mAbs) and/or their excipients.
- •Active, known or suspected autoimmune disease. Patients with vitiligo, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger should not be excluded. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
- •Treatment with cytotoxic or targeted antineoplastics within 3 weeks of initiation of study treatment. For cytotoxic agents that have major delayed toxicity a washout period of one cycle is indicated (examples are nitrosoureas and mitomycin C which typically require a 6 week washout). Prior antibodies or immunotherapies require a 6 week washout.
- •Patients receiving systemic chronic steroid therapy or any immunosuppressive therapy (≥ 10mg/day prednisone or equivalent). Topical, inhaled, nasal and ophthalmic steroids are allowed.
- •Active infection requiring systemic antibiotic therapy.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
FAZ053 single agent
干预措施: FAZ053 (Drug)
FAZ053 + PDR001
干预措施: FAZ053 (Drug)
FAZ053 + PDR001
干预措施: PDR001 (Drug)
结局指标
主要结局
Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: throughout the study and up to 150 days after end of treatment (up to approximately 46 months)
Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs) and laboratory parameters qualifying and reported as AEs.
Incidence of Dose Limiting Toxicities (DLTs)
时间窗: 21 days (single agent FAZ053) and 42 days (FAZ053+PDR001)
A DLT is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first 21 days of treatment with FAZ053 alone or within the first 42 days when FAZ053 is given in combination with PDR001 during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Dose interruptions and reductions
时间窗: Up to approximately 41 months
Number of participants with dose interruptions and reductions as a measure of tolerability.
Dose intensity
时间窗: Up to approximately 41 months
Dose intensity is defined as actual dose received divided by actual duration of exposure.
次要结局
- Concentration of anti-FAZ053 and anti-PDR001.(41 months)
- Presence of anti-FAZ053 and anti-PDR001.(41 months)
- Receptor Occupancy (RO) profiles when FAZ053 is given as single agent.(41 months)
- Total soluble/shed PD-L1 concentration-time profiles when FAZ053 is given as single agent and for FAZ053 in combination with PDR001.(41 months)
- Serum concentration-time profiles of FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)
- Histopathology of tumor infiltrating lymphocytes (TILs) by eosin (H&E) stain.(41 months)
- Overall response rate (ORR) per RECIST v1.1(41 months)
- Histopathology of tumor infiltrating lymphocytes (TILs) by hematoxylin.(41 months)
- Best overall response per RECIST v1.1(41 months)
- Disease control rate per RECIST 1.1(41 months)
- Progression free survival (PFS) per RECIST 1.1(41 months)
- Duration of response per RECIST 1.1(41 months)
- Overall response rate (ORR) per immune related Response Criteria (irRC).(41 months)
- Progression free survival (PFS) per immune related Response Criteria (irRC).(41 months)
- Characterization of Tumor Infiltrating Lymphocytes (TILs) by Immunohistochemistry (IHC)(41 months)
- Characterization of myeloid cell infiltrate by IHC.(41 months)
- Area under the curve (AUC) for FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)
- Cmax for FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)
- Tmax for FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)
- Half-life for FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)
- Clast for FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)
- Tlast for FAZ053 as single agent and FAZ053 in combination with PDR001.(41 months)