An Open-label, Phase 1, Multicentre Platform Study to Evaluate the Safety and Preliminary Anti-tumour Activity of NT-175 in Human Leukocyte Antigen-A*02:01-Positive Adult Participants With Advanced Malignancies That Are Positive for the TP53 R175H Mutation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 45
- 试验地点
- 23
- 主要终点
- Module 1, Part 1: Safety of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours
研究概览
简要总结
Phase I Study of NT-175, an autologous T cell therapy product genetically engineered to express an HLA-A*02:01-restricted T cell receptor (TCR), targeting TP53 R175H mutant malignancies
详细描述
This is a Phase 1, open-label, multicentre platform study to evaluate the safety and preliminary antitumour activity of NT-175 in HLA-A*02:01 participants with advanced malignancies that are positive for the TP53 R175H mutation.
Dose Escalation will investigate escalating doses of NT-175 in adult subjects with eligible histologies and will evaluate the safety and MTD and/or RDE/RP2D.
Cohort expansion will further evaluate the safety and preliminary anti-tumour activity at or below the MTD in disease specific histologies and determine the RP2D.
Dose Expansion will further evaluate the preliminary anti-tumour activity and safety of NT-175 at the RP2D in disease specific settings.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •Subjects must be at least 18 years of age
- •Subject must be diagnosed with one of the histologies below:
- •Colorectal adenocarcinoma
- •Pancreatic adenocarcinoma
- •Breast cancer
- •Ovarian cancer
- •Any other solid tumor
- •Tumors must harbor a TP53 R175H variant mutation and subject must be HLA-A*02:01 positive (at least 1 allele)
- •Subject has advanced solid cancer, defined as unresectable, advanced, and/or metastatic disease (Stage III or IV) after at least 1 line of approved systemic standard of care (SOC) treatment regimen and for which there are no available curative treatment options.
- •Subject has at least 1 measurable lesion
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Adequate hematological, renal, hepatic, pulmonary, and cardiac function
排除标准
- •Any another primary malignancy within the 3 years prior to enrollment
- •Known, active primary central nervous system (CNS) malignancy
- •History of prior adoptive cell and gene therapy, allogeneic stem cell transplant or solid organ transplantation.
- •History of clinically significant cardiac disease within the 6 months prior to enrollment or heart failure at any time prior to enrollment.
- •Systemic therapy within at least 2 weeks or 3 half-lives, whichever is shorter, prior to enrollment.
- •Any form of primary immunodeficiency.
- •Known to have Li-Fraumeni syndrome or is known to have relatives who are diagnosed with Li-Fraumeni syndrome.
- •Key Inclusion Criteria (Module 2 - hematological malignancies)
- •At least 18 years of age
- •Diagnosis of AML or MDS that allows for efficacy assessments
- •Confirmation of TP53 R175H variant mutation in cancer cells
- •Subject must be HLA-A*02:01 positive (at least 1 allele)
- •ECOG performance status of 0 to 1
- •Key Exclusion Criteria (Module 2 - hematological malignancy)
- •Acute promyelocytic leukaemia or isolated extramedullary disease
- •Another primary malignancy within 2 years (with exceptions)
- •HSCT within 100 days or immunosuppression for GvHD within 4 weeks
- •History of CNS or other extramedullary leukaemic involvement unless a lumbar puncture is negative for leukemic cells
- •Prior stroke, ischemic attack, significant cardiac disease, heart failure
- •Prior adoptive modified cell therapy
- •Known to have Li-Fraumeni syndrome or is known to have relatives who are diagnosed with Li-Fraumeni syndrome.
研究组 & 干预措施
NT-175 for advanced malignancies
TCR T cell therapy product
干预措施: NT-175 (Biological)
结局指标
主要结局
Module 1, Part 1: Safety of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours
时间窗: 28 days after infusion
Incidence of dose-limiting toxicities (DLTs) after the infusion of NT-175
Module 1, Part 1: Safety of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours
时间窗: Up to 24 months post-infusion
Incidence of Treatment Emergent Adverse Events (TEAE) Serious Adverse Events (SAE)
Module 1, Part 2: Preliminary anti-tumour activity of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours
时间窗: Up to 24 months after infusion
Per RECIST v1.1 determined by Investigator assessment: * Objective Response Rate (ORR) * Best Overall Response (BOR) * Duration of Response (DOR) * Clinical Benefit Rate (CBR) * Time to Response (TTR) * Progression-free survival (PFS) * Overall Survival (OS)
Module 2: Safety of NT-175 in participants with haematological malignancies
时间窗: Up to 28 days after infusion
\- Incidence of dose-limiting toxicities (DLTs) after the infusion of NT-175
Module 2: Safety of NT-175 in participants with haematological malignancies
时间窗: Up to 24 months after infusion
* Incidence of Treatment Emergent Adverse Events (TEAE) * Serious Adverse Events (SAE)
次要结局
- Module 1, Part 1: Preliminary anti-tumor activity of NT-175 in participants with unresectable, advanced, and/or metastatic solid tumours(Up to 24 months after infusion)
- Module 2: Evaluate preliminary anti-tumour activity in participants with AML or MDS(Up to 24 months after infusion)