A Phase 2, Randomized, Open-label Study of VVD-133214 in COmbination With Pembrolizumab Compared to Pembrolizumab Monotherapy in Participants With Advanced Colorectal Adenocarcinoma (CRC) Harboring Microsatellite Instability (MSI) and/or Deficient Mismatch Repair (DMMR)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 140
- 试验地点
- 243
- 主要终点
- Landmark progression-free survival (PFS) rate at 6 months, as assessed by the investigator
研究概览
简要总结
Researchers are looking for a better way to treat people with advanced colorectal cancer.
Colorectal cancer (cancer of the colon or rectum) is one of the most common cancers worldwide. Treatments include surgery, chemotherapy, radiotherapy, and immunotherapy; however, these treatments do not work for everyone, may cause serious adverse events or may stop working eventually. New treatments and treatment combinations are needed, especially for cancers that cannot be removed with surgery or that have spread to other parts of the body (called advanced or metastatic cancer).
Cells normally repair themselves when mistakes happen as they divide. But in some people with cancer, the repair system does not work properly because of a problem called dMMR (deficient mismatch repair). As a result, mistakes build up in the cell's DNA, leading to a condition called MSI (microsatellite instability). Over time, these changes can cause cells to grow and behave abnormally, contributing to the development and growth of cancer.
To survive, some cancer cells with dMMR or MSI rely on a protein called Werner helicase. This protein helps repair some of the DNA damage allowing them to keep growing. Because these cancer cells depend more on Werner helicase than healthy cells, blocking this protein may help stop cancer cells from surviving while having less effect on healthy cells.
The study drug, VVD-133214, is designed to block the Werner helicase protein. Blocking this protein may help stop cancer cells from growing, while causing less harm to healthy cells. VVD-133214 is being studied in combination with pembrolizumab, an approved immunotherapy that helps the immune system recognize and attack cancer cells.
This study will test the combination of VVD-133214 and pembrolizumab in people with advanced colorectal cancer with MSI and/or dMMR who have not yet received treatment for their advanced disease. The study aims to find the best dose of VVD-133214 in combination with pembrolizumab and to test whether the combination is more effective than pembrolizumab alone.
Participants will receive treatment with VVD-133214 for as long as it can help them and does not cause serious adverse events. Treatment with pembrolizumab will stop after two years. Participants can also stop treatment at any time.
During the study, participants will have regular visits with the study doctor for tests, scans, and check-ups. These visits help check how well the cancer is responding to the treatment and monitor the participants' health.
The study will also monitor adverse events, which are any new or worsening medical problems that can happen during the study. Doctors record all adverse events, irrespective of whether the study doctor believes they are related to the study treatments, to help ensure participants' safety throughout the study.
After stopping treatment, participants will return for follow-up visits: 30 days after their last dose of VVD-133214 and/or 100 days after their last dose of pembrolizumab. After that, participants will have long-term follow-up visits every 90 days for as long as they agree to continue participating in follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 known microsatellite instability (MSI) and/or deficient mismatch repair (dMMR) tumor status confirmed per local standard of care (SoC), and have histologically or cytologically documented advanced (unresectable and/or metastatic) colorectal adenocarcinoma (CRC)
- •No prior systemic treatment for metastatic disease and not amenable to curative resection
- •Participants must have documented MSI and/or dMMR tumor status determined as part of the routine diagnostic workup in a certified laboratory
- •Availability of formaldehyde-fixed paraffin-embedded (FFPE) archival tumor tissue for submission to Sponsor/central laboratory for retrospective central testing including a copy of a redacted pathology report if available
- •Presence of measurable disease according to RECIST v1.1
- •Adequate hematologic and end-organ function, defined using laboratory results obtained within 14 days prior to first dose of study treatment
- •Females of childbearing potential must have negative serum pregnancy test before starting study treatment
排除标准
- •Prior systemic treatment for advanced CRC. Participants may have received prior adjuvant chemotherapy as long as disease progression occurred at least 12 months after the last dose of adjuvant treatment
- •Prior treatment with adjuvant immunotherapy (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or anti-CTLA-4 agent, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents, etc.)
- •Known active or uncontrolled central nervous system (CNS) or brain metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) and/or carcinomatous meningitis
- •Patients with active or history of autoimmune disease or immune deficiency that has required treatment in past 2 years
- •History of malignancy other than CRC, within 5 years prior to screening. Participants with Lynch syndrome are not excluded.
- •Participants requiring treatment with systemic immunosuppressive medication (such as corticosteroids) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
- •Participants with active hepatitis B, hepatitis C or HIV
- •Participants with known Werner Syndrome (WRN)
- •Prior treatment with any WRN helicase inhibitor
研究组 & 干预措施
VVD-133214 Dose 2 + Pembrolizumab
Participants will receive VVD-133214 in combination with pembrolizumab
干预措施: VVD-133214 (Drug)
VVD-133214 Dose 1 + Pembrolizumab
Participants will receive VVD-133214 in combination with pembrolizumab
干预措施: VVD-133214 (Drug)
VVD-133214 Dose 1 + Pembrolizumab
Participants will receive VVD-133214 in combination with pembrolizumab
干预措施: Pembrolizumab (Drug)
Pembrolizumab
Participants will receive pembrolizumab only (monotherapy)
干预措施: Pembrolizumab (Drug)
VVD-133214 Dose 2 + Pembrolizumab
Participants will receive VVD-133214 in combination with pembrolizumab
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Landmark progression-free survival (PFS) rate at 6 months, as assessed by the investigator
时间窗: From start of study treatment until end of follow-up (up to approximately 36 months)
Defined as the proportion of participants who are alive and free from disease progression as per RECIST v1.1
次要结局
- Incidence and severity of Adverse Events (AEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0)(From start of study treatment up to 30 days following the last dose of study drug (100 days after last administration of pembrolizumab))
- Recommended Phase 2 Dose (RP2D) of VVD-133214 in combination with pembrolizumab(From start of study treatment until end of follow-up (up to approximately 36 months))
- Maximum plasma concentration observed (Cmax) following single and multiple doses of VVD-133214(Predose and multiple timepoints post-dose, up to approximately 36 months)
- Time of maximum plasma concentration observed (Tmax) following single and multiple doses of VVD-133214(Predose and multiple timepoints post-dose, up to approximately 36 months)
- Area under the plasma concentration-time curve (AUC) following single and multiple doses of VVD-133214(Predose and multiple timepoints post-dose, up to approximately 36 months)
- Overall response rate (ORR) according to RECIST v1.1 as assessed by the Investigator(From start of study treatment until end of follow-up (up to approximately 36 months))
- Disease control rate (DCR) according to RECIST v1.1 as assessed by the Investigator(From start of study treatment until end of follow-up (up to approximately 36 months))
- Duration of response (DOR) according to RECIST v1.1 as assessed by the Investigator(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))
- Median progression-free survival (mPFS) according to RECIST v1.1 as assessed by the Investigator(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))