A Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Anti-tumor Activity of TNG462 as a Single Agent and in Combination in Patients With MTAP-deleted Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 225
- 试验地点
- 52
- 主要终点
- Phase 1 Maximum Tolerated Dose
研究概览
简要总结
This is a first in human study in patients with advanced or metastatic solid tumors known to have an MTAP deletion. The first part of the study is an open-label, dose escalation and the second part is an open label dose expansion in specific MTAP-deleted tumor types. The study drug, TNG462, is a selective PRMT5 inhibitor administered orally. The study is planned to treat up to 225 participants.
详细描述
This is a Phase 1/2 multi-center, open label study in solid tumor patients who have a confirmed homozygous MTAP deletion in their tumor. The Phase 1 portion is a dose escalation study of oral TNG462 administered as a single agent and in combination with pembrolizumab in patients with confirmed MTAP-deleted solid tumors. In Phase 2, 6 expansion arms defined by confirmed MTAP-deleted tumor types will enroll in parallel at the RP2D(s) of TNG462 and in combination. In both parts of the study participants who tolerate the drug may continue treatment until disease progression.
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
- •Age: ≥18 years-of-age at the time of signature of the main study ICF
- •Performance status: ECOG Performance Score of 0 to 1
- •Confirmed histologic or cytologic diagnosis of a locally advanced, metastatic, and/or unresectable solid tumor
- •Prior standard therapy, as available
- •Documented bi-allelic (homozygous) deletion of MTAP in a tumor detected by next- generation sequencing or absence of MTAP protein in a tumor detected by IHC.
- •Adequate organ function/reserve per local labs
- •Adequate liver function per local labs
- •Adequate renal function per local labs
- •Negative serum pregnancy test result at screening
- •Written informed consent must be obtained according to local guidelines
排除标准
- •Known allergies, hypersensitivity, or intolerance to TNG462, or its excipients or to pembrolizumab in the combination treatment arms
- •Uncontrolled intercurrent illness that will limit compliance with the study requirements
- •Active infection requiring systemic therapy
- •Currently participating in or has planned participation in a study of another investigational agent or device
- •Impairment of GI function or disease that may significantly alter the absorption of oral TNG462
- •Active prior or concurrent malignancy.
- •Central nervous system metastases associated with progressive neurological symptoms
- •Current active liver disease from any cause
- •Known to be HIV positive, unless all of the following criteria are met:
- •CD4+ count ≥300/μL
- •Undetectable viral load
- •Receiving highly active antiretroviral therapy
- •Clinically relevant cardiovascular disease
- •A female patient who is pregnant or lactating
- •Patient is unwilling or unable to comply with the scheduled visits, drug administration plan, laboratory tests, biopsy, or other study procedures and study restrictions
- •Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, may affect the safety of the patient or impair the assessment of study results
研究组 & 干预措施
Dose Expansion in Pancreatic Ductal Adenocarcinoma
Participants with MTAP-deleted pancreatic ductal adenocarcinoma will receive TNG462 at the identified RP2D(s)
干预措施: TNG462 (Drug)
Dose Expansion in Sarcoma
Participants with MTAP-deleted sarcoma (soft tissue or bone) will receive TNG462 at the identified RP2D(s)
干预措施: TNG462 (Drug)
Dose Expansion in NSCLC in Combination with Pembrolizumab
Participants NSCLC (squamous and non squamous) MTAP-deleted solid tumors will receive TNG462 at the identified RP2D(s)
干预措施: TNG462 (Drug)
Dose Expansion in Solid Tumors
Participants with other MTAP-deleted solid tumors will receive TNG462 at the identified RP2D(s)
干预措施: TNG462 (Drug)
Dose Expansion in Mesothelioma
Participants with MTAP-deleted mesothelioma will receive TNG462 at the identified RP2D(s)
干预措施: TNG462 (Drug)
Dose Expansion in NSCLC in Combination with Pembrolizumab
Participants NSCLC (squamous and non squamous) MTAP-deleted solid tumors will receive TNG462 at the identified RP2D(s)
干预措施: Pembrolizumab (Drug)
Dose Escalation
Participants with MTAP-deleted solid tumors (excluding primary CNS) will receive escalating doses of TNG462 single agent and in combination with pembrolizumab to estimate the MTD
干预措施: TNG462 (Drug)
Dose Escalation
Participants with MTAP-deleted solid tumors (excluding primary CNS) will receive escalating doses of TNG462 single agent and in combination with pembrolizumab to estimate the MTD
干预措施: Pembrolizumab (Drug)
Dose Expansion in NSCLC
Participants with MTAP-deleted NSCLC (squamous and non squamous) will receive TNG462 at the identified RP2D(s)
干预措施: TNG462 (Drug)
结局指标
主要结局
Phase 1 Maximum Tolerated Dose
时间窗: 28 days and 21 days
To determine the maximum tolerated dose (MTD) of TNG462 when administered as a single agent and in combination with pembrolizumab
Phase 1 Dosing Schedule
时间窗: 28 days
To determine the dosing schedule of TNG462
Phase 2 Anti-neoplastic Activity
时间窗: 16 weeks and 18 weeks
To assess anti-neoplastic activity of TNG462 administered single agent and in combination with pembrolizumab in patients with MTAP-deleted advanced solid tumors by RECIST v1.1, iRECIST or mRECIST v1.1
次要结局
- Phase 1 Anti-neoplastic Activity(16 weeks)
- Phase 1 and 2 Adverse Event Profile(28 days and 21 days)
- Phase 1 and 2 Volume of Distribution(16 days)
- Phase 1 and 2 Concentration versus Time Curve(16 days)
- Phase 1 and 2 Time to Achieve Maximal Plasma Concentration(16 days)
- Phase 1 and 2 Maximum Observed Plasma Concentration(16 days)
- Phase 1 and 2 Terminal Elimination Half-life(16 days)
- Phase 1 and 2 SDMA Levels(28 days)
- Phase 1 and 2 Total Plasma Clearance(16 days)