NCT06004245招募中1 期
A Phase I, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Anti-Tumor Activity of VVD-133214 as Monotherapy and in Combination in Participants With Advanced Solid Tumors Harboring Microsatellite Instability (MSI) and/or Deficient Mismatch Repair (dMMR)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 280
- 试验地点
- 71
- 主要终点
- Incidence of Adverse Events, with Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0)
研究概览
简要总结
This is a first-in-human, Phase I, open-label, multicenter, dose-escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of VVD-133214 monotherapy, and in combination with bevacizumab or pembrolizumab, in participants with microsatellite instability (MSI) and/or deficient mismatch repair (dMMR) advanced solid tumors. VVD-133214 is an oral drug that acts on a protein called Werner (WRN), which may promote the growth of cancers that are MSI and/or dMMR. By acting on WRN, VVD-133214 may be able to block the growth of these types of cancer.
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
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- •Have a microsatellite instability (MSI) and/or deficient mismatch repair (dMMR), histologically or cytologically documented advanced (unresectable and/or metastatic) solid tumor; For the combination with bevacizumab only: advanced, or metastatic colorectal adenocarcinoma (CRC) treated with at least 2 but no more than 3 prior lines of systemic therapy for the treatment of advanced CRC; For the combination with pembrolizumab only: Histologically confirmed locally advanced, or metastatic CRC with no prior systemic treatment for metastatic disease and not amenable to surgery
- •Have received and then progressed following, or are intolerant to, standard therapy in the advanced setting
- •Presence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- •Life expectancy of at least (≥)12 weeks
- •Availability of formaldehyde-fixed paraffin-embedded (FFPE) archival tumor tissue for submission to Sponsor/central laboratory for retrospective central testing; for participants without archival tissue, a biopsy from either primary or metastatic tumor lesion, deemed medically feasible, must be taken
- •Adequate hematologic, end-organ, and cardiovascular function, as defined in the protocol
排除标准
- •Inability or unwillingness to swallow pills
- •Malabsorption syndrome or other condition that would interfere with enteral absorption
- •Known hypersensitivity or intolerance to ingredients from the study drug formulation including patients with rare genetic disorders such as galactosaemia, glucose-galactose intolerance or congenital lactase deficiency
- •Known uncontrolled central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) and/or carcinomatous meningitis
- •Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis and atypical mycobacterial disease), parasitic, or other infection (excluding fungal infections of nail beds), or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 2 weeks prior to the start of drug administration (related to the completion of the course of antibiotics, except if for tumor fever) or 6 months for any intracranial abscess
- •Has a positive test at screening for hepatitis B virus, hepatitis C virus, or for human immodeficiency virus (HIV), per local diagnostic standard and in accordance with local laws and regulations
- •Uncontrolled diabetes or symptomatic hyperglycemia (i.e., well controlled defined as a screening hemoglobin A1c <8% and no urinary ketoacidosis)
- •Significant cardiovascular/cerebrovascular disease within 6 months prior to Day 1 of study drug administration
- •Alcohol or drug dependence or abuse
- •Patients with known Werner (WRN) syndrome
- •Prior treatment with any WRN helicase inhibitor
- •Treatment with moderate or strong CYP3A4 inducers within 14 days prior to initiation of study treatment
- •Treatment with moderate or strong CYP3A4 or P-glycoprotein inhibitors within 14 days prior to initiation of study treatment
- •Pregnancy, breastfeeding, or intention of becoming pregnant during the study
- •Additional Exclusion Criteria for the Combination with Bevacizumab Only:
- •Had major surgery within 4 weeks prior to study drug administration
- •Deep venous thrombosis (DVT) or pulmonary embolism (PE) within 12 weeks prior to study drug administration
- •Known coagulopathy that increases the risk of bleeding
- •Patients with Grade 2+ proteinuria (exception: if 24-hour urinary protein is less than 1.0 gm/24 hours)
- •Additional Exclusion Criteria for the Combination with Pembrolizumab Only:
- •Active or history of autoimmune disease or immune deficiency with some exceptions
- •History of interstitial lung disease or pneumonitis
- •Treatment with systemic immunosuppressive medication (such as corticosteroids) within 2 weeks prior to initiation of study treatment with some exceptions
- •Treatment with organ transplant/graft tissue
研究组 & 干预措施
VVD-133214 Dose Escalation
Experimental
干预措施: VVD-133214 (Drug)
VVD-133214 Monotherapy Expansion
Experimental
干预措施: VVD-133214 (Drug)
VVD-133214 + Pembrolizumab Expansion
Experimental
干预措施: VVD-133214 (Drug)
VVD-133214 + Pembrolizumab Expansion
Experimental
干预措施: Pembrolizumab (Drug)
VVD-133214 + Bevacizumab Expansion
Experimental
干预措施: VVD-133214 (Drug)
VVD-133214 + Bevacizumab Expansion
Experimental
干预措施: Bevacizumab (Drug)
结局指标
主要结局
Incidence of Adverse Events, with Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0)
时间窗: From first dose of study drug(s) until 30 days after the final dose of VVD-133214 or 90 days after last dose of pembrolizumab
Incidence of Dose-Limiting Toxicities
时间窗: Cycle 1 (1 cycle is 3 weeks)
次要结局
- Objective Response Rate(From start of study treatment until end of follow-up (up to approximately 36 months))
- Disease Control Rate(From start of study treatment until end of follow-up (up to approximately 36 months))
- Duration of Response(From the time of first occurrence of a documented response until the time of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months))
- Progression-Free Survival, as Assessed by the Investigator(From start of study treatment to the first occurrence of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months))
- Overall Survival(From start of study treatment to the time of death from any cause (up to approximately 36 months))
- Volume of Distribution (V/F) of VVD-133214(At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months))
- Progression-Free Survival, as Assessed by the Investigator(From start of study treatment to the first occurrence of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months))
- Overall Survival(From start of study treatment to the time of death from any cause (up to approximately 36 months))
- Maximum Plasma Concentration Observed (Cmax) of VVD-133214(At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months))
- Time of Maximum Plasma Concentration Observed (Tmax) of VVD-133214(At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months))
- Area Under the Plasma Concentration-Time Curve (AUC) of VVD-133214(At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months))
- Apparent Oral Clearance (CL/F) of VVD-133214(At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months))
- Terminal Half-Life (T1/2) of VVD-133214(At prespecified timepoints in Cycles 1, 2, and 3, and every 2 cycles thereafter (1 cycle is 3 weeks) until last dose of study drug (up to approximately 15 months))
- Objective Response Rate(From start of study treatment until end of follow-up (up to approximately 36 months))
- Disease Control Rate(From start of study treatment until end of follow-up (up to approximately 36 months))
- Duration of Response(From the time of first occurrence of a documented response until the time of documented disease progression or death from any cause, whichever occurs first (up to approximately 36 months))
研究者
研究点 (71)
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相关资讯
Vividion's WRN Inhibitor VVD-214 Shows Promise for MSI-High Cancers in Journal of Medicinal Chemistry Publication- Vividion Therapeutics published the discovery of VVD-214, a covalent Werner helicase inhibitor, on the cover of Journal of Medicinal Chemistry, marking the first covalent inhibitor of this target in clinical development.
- Preclinical studies demonstrated that VVD-214 was well tolerated and led to robust tumor regression in multiple patient-derived xenograft mouse models of MSI-high colorectal cancer.
- The compound is currently being evaluated in a Phase I clinical trial as monotherapy and in combination with pembrolizumab for patients with MSI-high or mismatch repair deficient cancers.
- VVD-214 exploits the dependency of MSI-high cancer cells on WRN-mediated DNA repair, leading to selective tumor cell death while sparing healthy tissue.8 months agoVividion Secures Exclusive Rights to First-in-Class WRN Inhibitor VVD-214 for MSI-High Cancers- Vividion Therapeutics has secured exclusive worldwide rights to develop VVD-214, the only clinical-stage covalent inhibitor of Werner helicase (WRN) currently in development globally.
- Preliminary data from a first-in-human Phase I study presented at AACR showed VVD-214 is well tolerated with promising signs of activity in solid tumors with high microsatellite instability.
- The compound targets a synthetic lethal pathway in MSI-high cancers including colorectal, endometrial, ovarian, and gastric tumors, addressing significant unmet medical need in patients who relapse or become refractory to immune checkpoint inhibitors.last year