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临床试验/NCT06188702
NCT06188702进行中（未招募）1 期

A Phase 1/2, Open-label, Multicenter Clinical Trial Investigating the Safety, Tolerability, Pharmacokinetics, and Antineoplastic Activity of S095035 (MAT2A Inhibitor) as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Homozygous Deletion of MTAP

Servier Bio-Innovation LLC38 个研究点 分布在 8 个国家目标入组 60 人开始时间: 2024年4月29日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
1 期
状态
进行中（未招募）
入组人数
60
试验地点
38
主要终点
Dose limiting toxicities (DLTs)
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a first-in-human Phase 1/2, multicenter, open-label study of S095035 as single-agent, or in combination with TNG462 in adult participants with advanced or metastatic solid tumors with homozygous deletion of MTAP who have failed to respond to or have progressed after at least 1 prior treatment regimen, and for whom additional effective standard treatment is not available. S095035 is an oral methionine adenosyltransferase 2A [MAT2A] inhibitor. TNG462 is a protein arginine N-methyltransferase 5 [PRMT5] inhibitor.

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

  • •Estimated life expectancy ≥3 months.
  • •ECOG PS 0-1
  • •Participants able to comply with highly effective method of birth control requirements.
  • •Participants with histologically confirmed advanced or metastatic solid tumor's (excluding central nervous system tumors other than IDHwt glioblastoma), with measurable disease as per RECIST 1.1 or RANO 2.0 criteria for participants with IDHwt glioblastoma, that have progressed after at least one prior treatment regimen given for advanced/metastatic disease, and for whom additional effective standard therapy is not available. Patients in China with IDHwt glioblastoma will not be included.
  • •Participants with pre-existing documented MTAP homozygous gene deletion in their tumor tissue, determined using a next generation sequencing in vitro diagnostic test prior to screening.
  • •Phase 1 only - Participants (except IDHwt glioblastoma) willing to undergo paired fresh biopsy (pre-treatment and on-treatment) procedure. Exceptions may be made for feasibility and safety concerns. IDHwt glioblastoma must provide archival tissue from most recent surgery or biopsy.
  • •Adequate organ functions.
  • •Phase 2 only - Participants in dose expansion, except those with IDHwt glioblastoma, must provide newly collected tumor biopsies at screening. If not medically feasible archival tissue may be used, provided it was collected within 3 months before study entry and no treatment has been received since the most recent biopsy.
  • •Phase 2 only - Participants with IDHwt glioblastoma must provide archival tissue from their most recent surgery or biopsy, collected before screening.
  • •Phase 2 only - Participants in China who are to be considered for enrollment in the single agent dose expansion Arms and who have a pre-existing, documented cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous gene deletion in their tumor tissue (confirmed by an NGS IVD test), but do not have homozygous MTAP deletion reported, will need to be pre-screened to confirm homozygous MTAP deletion. Pre screening for homozygous MTAP deletion will be conducted using a central NGS IVD test using an archival tumor tissue, preferably the most recent and not older than 3 years.
  • •Phase 2 Arm 1a only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with homozygous deletion of MTAP, with measurable disease as per RECIST version 1.1, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting.
  • •Phase 2 Arm 1b only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting.
  • •Phase 2 Arm 1c only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting.
  • •Phase 2 Arm 1d only - Participants with any other locally advanced or metastatic malignancies with homozygous deletion of MTAP, who have received and progressed of experienced recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting.
  • •Phase 2 Arm 2a only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of care systemic therapy in the advanced/metastatic setting.
  • •Phase 2 Arm 2b only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced gastroesophageal cancer with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting.
  • •Phase 2 Arm 2c only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy in the advanced/metastatic setting.

排除标准

  • •Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the study drug.
  • •Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's Medical monitor and investigator agree and document that it should not be exclusionary.
  • •Known prior severe hypersensitivity to any component of the study drug formulation.
  • •Major surgery within 4 weeks prior to the first study drug administration or participants who have not recovered from side effects of the surgery.
  • •Have a known history of Gilbert's syndrome.
  • •Participants with a known clinically significant cardiovascular disease or condition.
  • •Participants with thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to first IMP administration.
  • •Active brain metastases.
  • •Participants who have received systemic anticancer treatment or radiotherapy less than 2 weeks before the first dose of study drug
  • •Pregnant or lactating women.
  • •Women of childbearing potential who have a positive pregnancy test within 7 days prior to the first day of study drug administration.
  • •History of gastrointestinal perforation and /or fistula or aorto-esophageal fistula within 6 months prior to first study drug intake.
  • •Severe or uncontrolled active acute or chronic infection.
  • •Participants who have already received a MAT2A or PRMT5 inhibitor.
  • •A medical condition that results in increased clinically significant photosensitivity (e.g., solar urticaria, lupus erythematosus, etc.).
  • •Participants who are scheduled to receive the S095035-TNG462 combination, with a known clinically significant ophthalmologic disease, including:
  • •Prior history of drug-induced or toxic retinopathy or optic neuropathy
  • •Uncontrolled glaucoma
  • •Pre-existing macular degeneration
  • •Ongoing Grade ≥2 retinopathy, optic neuropathy, or optic neuritis
  • •Other known active retinal pathology

研究组 & 干预措施

Phase 2 Arm 2b Gastroesophageal - S095035-TNG462 combination dose expansion

Experimental

干预措施: TNG462 (Drug)

Phase 1 Arm 1 - S095035 single-agent dose escalation

Experimental

干预措施: S095035 (Drug)

Phase 1 Arm 2 - S095035-TNG462 combination dose escalation

Experimental

干预措施: S095035 (Drug)

Phase 1 Arm 2 - S095035-TNG462 combination dose escalation

Experimental

干预措施: TNG462 (Drug)

Phase 2 Arm 1a NSCLC - S095035 single-agent dose expansion

Experimental

Non-Small Cell Lung Cancer

干预措施: S095035 (Drug)

Phase 2 Arm 1b BTC - S095035 single-agent dose expansion

Experimental

Biliary Tract Cancer

干预措施: S095035 (Drug)

Phase 2 Arm 1c PDAC - S095035 single-agent dose expansion

Experimental

Pancreatic Ductal Adenocarcinoma

干预措施: S095035 (Drug)

Phase 2 Arm 1d Basket arm - S095035 single-agent dose expansion

Experimental

干预措施: S095035 (Drug)

Phase 2 Arm 2a BTC - S095035-TNG462 combination dose expansion

Experimental

Biliary Tract Cancer

干预措施: S095035 (Drug)

Phase 2 Arm 2a BTC - S095035-TNG462 combination dose expansion

Experimental

Biliary Tract Cancer

干预措施: TNG462 (Drug)

Phase 2 Arm 2b Gastroesophageal - S095035-TNG462 combination dose expansion

Experimental

干预措施: S095035 (Drug)

Phase 2 Arm 2c PDAC - S095035-TNG462 combination dose expansion

Experimental

Pancreatic Ductal Adenocarcinoma

干预措施: S095035 (Drug)

Phase 2 Arm 2c PDAC - S095035-TNG462 combination dose expansion

Experimental

Pancreatic Ductal Adenocarcinoma

干预措施: TNG462 (Drug)

结局指标

主要结局

Dose limiting toxicities (DLTs)

时间窗: Through cycle 1 (each cycle is 28 days)

Phase 1 only

Total number of adverse events (AEs)

时间窗: Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years

Phase 1 only

Total number of serious adverse events (SAEs)

时间窗: Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years

Phase 1 only

Objective response rate (ORR)

时间窗: Through the end of the study (approximately 5 years)

Phase 2 only; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment and by blinded independent central review (BICR)

次要结局

  • Area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t)(Through the last dose of study treatment (approximately 5 years))
  • AUC from 0 to infinity (AUC0-∞)(Through the last dose of study treatment (approximately 5 years))
  • AUC over 1 dosing interval at steady state (AUCtau,ss)(Through the last dose of study treatment (approximately 5 years))
  • Time to maximum concentration (Tmax)(Through the last dose of study treatment (approximately 5 years))
  • Maximum concentration (Cmax)(Through the last dose of study treatment (approximately 5 years))
  • Trough concentration (Ctrough)(Through the last dose of study treatment (approximately 5 years))
  • Half-life (t½)(Through the last dose of study treatment (approximately 5 years))
  • Apparent volume of distribution (Vd/F)(Through the last dose of study treatment (approximately 5 years))
  • Apparent clearance (CL/F)(Through the last dose of study treatment (approximately 5 years))
  • Change from baseline in plasma concentrations of S-adenosylmethionine (SAM) and/or tumor symmetric dimethylarginine (SDMA) residues during treatment(Through the last dose of study treatment (approximately 5 years))
  • Objective response rate (ORR)(Through the end of the study (approximately 5 years))
  • Best overall response (BOR)(Through the end of the study (approximately 5 years))
  • Clinical benefit rate (CBR)(Through the end of the study (approximately 5 years))
  • Duration of response (DOR)(Through the end of the study (approximately 5 years))
  • Time to response (TTR)(Through the end of the study (approximately 5 years))
  • Progression-free Survival (PFS)(Through the end of the study (approximately 5 years))
  • Overall Survival (OS)(Through the end of the study (approximately 5 years))
  • Total number of adverse events (AEs)(Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years)
  • Total number of serious adverse events (SAEs)(Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years)
  • Number of dose interruptions(Through the last dose of study treatment (approximately 5 years))
  • Number of dose reductions(Through the last dose of study treatment (approximately 5 years))
  • Dose intensity(Through the last dose of study treatment (approximately 5 years))

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (38)

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