An Open-Label, Multicenter, First-in-Human, Dose-Escalation, Phase 1 / 2 Study of INBRX-105 and INBRX-105 in Combination With Pembrolizumab in Patients With Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 160
- 试验地点
- 23
- 主要终点
- Frequency of adverse events of INBRX-105
研究概览
简要总结
This is a first-in-human, open-label, nonrandomized, four-part trial to determine the safety profile and identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of INBRX-105 and INBRX-105 in combination with Pembrolizumab. INBRX-105, a next generation bispecific antibody, targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor. INBRX-105 provides localized conditional T-cell co-stimulation through 4-1BB agonism.
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
- •Parts 1 and 3 (escalation cohorts; completed): Patients with locally advanced or metastatic non-resectable solid tumors, whose disease has progressed despite standard therapy and for whom no further standard therapy exists.
- •Part 2 (expansion cohorts): Patients with non-small cell lung cancer, cutaneous melanoma, head and neck squamous cell carcinoma or solid tumors amenable to paired biopsies, with locally advanced or metastatic, non-resectable disease, which has progressed despite standard therapy or for whom no standard or clinically acceptable therapy exists.
- •Part 4 relapsed or refractory to CPI cohorts: NSCLC, cutaneous melanoma, HNSCC, MSI/TMB-high or MMRd solid tumors
- •Part 4 CPI naive cohorts: locally advanced or metastatic, non-resectable NSCLC or HNSCC
- •Refractory or relapsed to anti-PD-1 or anti-PD-L1, and anti-CTLA4 if applicable (NOTE: For all tumor types with checkpoint inhibitor approvals) with exception of the treatment naive NSCLC cohort.
- •PD-L1 positivity by immunohistochemistry (IHC): Parts 1 and 3 (escalation cohorts) PD-L1 positivity is not required. Parts 2 and 4 (expansion cohorts): Combined Positive Score (CPS) or Tumor Proportion Score (TPS) above certain thresholds as defined per protocol.
- •Adequate hematologic, coagulation, hepatic and renal function as defined per protocol.
- •Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
排除标准
- •Prior exposure to 4-1BB agonists.
- •Receipt of any investigational product or any approved anticancer drug(s) or biological product(s) within 4 weeks prior to the first dose of study drug. Exceptions: Hormone replacement therapy, testosterone, or oral contraceptives. NOTE: Previous exposure to anti-PD-L1 checkpoint inhibitor requires a minimum washout period of 24 weeks prior to the first dose of study drug.
- •Hematologic malignancies (e.g., ALL, AML, MDS, CLL, CML, NHL, Hodgkin lymphoma and multiple myeloma).
- •Prior or concurrent malignancies. Exception: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of INBRX-
- •Known or active primary central nervous system (CNS) tumors, leptomeningeal disease and CNS metastases. Exception: Subjects with previously treated, asymptomatic, and clinically stable CNS metastases may be allowed study entry if certain criteria apply.
- •Grade ≥ 3 immune-related adverse events (irAEs) or irAE that lead to discontinuation of prior immunotherapy. Some exceptions as defined per protocol apply.
- •Active autoimmune disease or documented history of autoimmune disease that required systemic steroids or other immunosuppressive medications. Certain exceptions as defined in protocol apply.
- •Treatment with systemic immunosuppressive medications within 4 weeks prior to the first dose of study drug. Certain exceptions as defined in protocol apply.
- •History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). Exceptions as defined in protocol for expansion cohorts will apply.
- •History of hepatitis or cirrhosis (e.g., non-alcohol steatohepatitis, alcohol or drug-related, autoimmune, hepatitis B, or hepatitis C). Exceptions as defined in protocol for expansion cohorts will apply.
- •Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or other immunosuppressive medications.
- •Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, cerebrovascular accident, or other acute uncontrolled heart disease < 3 months; left ventricular ejection fraction (LVEF) < 50%; New York Heart Association (NYHA) Class III or IV congestive heart failure; or uncontrolled hypertension.
- •Active, hemodynamically significant pulmonary embolism within 3 months prior to enrollment on this trial.
- •Major surgery within 4 weeks prior to enrollment on this trial.
- •Anti-infectious drug treatments (i.e., antibiotics) within 4 weeks prior to the first dose of study drug.
- •Prior organ allograft transplantations or allogeneic peripheral blood stem cell (PBSC) or bone marrow (BM) transplantation.
研究组 & 干预措施
Single Agent Escalation
INBRX-105 will be escalated in patients with locally advanced or metastatic solid tumors.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Expansion Cohort Non-small Cell Lung Cancer
Patients will be treated with single-agent INBRX-105 at either the MTD or RP2D.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Expansion Cohort Melanoma
Patients will be treated with single-agent INBRX-105 at either the MTD or RP2D.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Expansion Cohort PD-L1 Positive Basket
Patients with gastric or gastro-esophageal junction adenocarcinoma, renal cell carcinoma, and urothelial (transitional) cell carcinoma will be treated with single-agent INBRX-105 at either the MTD or RP2D.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Expansion Cohort Nasopharyngeal or Oropharyngeal Carcinoma
Patients with head and neck squamous cell carcinoma (NPC or OPC) will be treated with single-agent INBRX-105 at either the MTD or RP2D.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
INBRX-105 Escalation in Combination with Pembrolizumab
INBRX-105 will be escalated in combination with Pembrolizumab in pateitns with locally advanced or metastatic solid tumors.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
INBRX-105 Escalation in Combination with Pembrolizumab
INBRX-105 will be escalated in combination with Pembrolizumab in pateitns with locally advanced or metastatic solid tumors.
干预措施: Pembrolizumab (Drug)
Combination Expansion Cohort Non-small Cell Lung Cancer
CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Combination Expansion Cohort Non-small Cell Lung Cancer
CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: Pembrolizumab (Drug)
Combination Expansion Cohort Melanoma
CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Combination Expansion Cohort Melanoma
CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: Pembrolizumab (Drug)
Combination Expansion Cohort Cohort PD-L1 Positive Basket
CPI-relapsed/refractory patients with head and neck squamous cell carcinoma, gastro-esophageal junction adenocarcinoma, renal cell carcinoma, and urothelial (transitional) cell carcinoma will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Combination Expansion Cohort Cohort PD-L1 Positive Basket
CPI-relapsed/refractory patients with head and neck squamous cell carcinoma, gastro-esophageal junction adenocarcinoma, renal cell carcinoma, and urothelial (transitional) cell carcinoma will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: Pembrolizumab (Drug)
Combination Expansion Cohort CPI Naive Non-small Cell Lung Cancer
CPI naive patients (PD-L1 IHC between 1 and 49%) will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
Combination Expansion Cohort CPI Naive Non-small Cell Lung Cancer
CPI naive patients (PD-L1 IHC between 1 and 49%) will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: Pembrolizumab (Drug)
Combination Expansion Cohort CPI Naive HNSCC
CPI naive patients (PD-L1 IHC >50%) will be treated with INBRX-105 in combination with Pembrolizumab.
干预措施: INBRX-105 - PDL1x41BB antibody (Drug)
结局指标
主要结局
Frequency of adverse events of INBRX-105
时间窗: Up to 2-3 years
Adverse events will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of INBRX-105
时间窗: Up to 2-3 years
The MTD and/or RP2D of INBRX-105 will be determined.
Severity of adverse events of INBRX-105
时间窗: Up to 2-3 years
Severity of adverse events will be assessed and assigned by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.
次要结局
- Time to Cmax (Tmax) of INBRX-105(Up to 2-3 years)
- Area under the serum concentration time curve (AUC) of INBRX-105(Up to 2-3 years)
- Maximum observed serum concentration (Cmax) of INBRX-105(Up to 2-3 years)
- Immunogenicity of INBRX-105(Up to 2-3 years)
- Trough observed serum concentration (Ctrough) of INBRX-105(Up to 2-3 years)