A Phase 1/2 Adaptive Study of DES-1357 in Participants With Deficient Mismatch Repair (dMMR) and/or Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer (mCRC)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 88
- 主要终点
- Part 2: Area Under the Curve (AUC) of DES-1357
研究概览
简要总结
This study is conducted sequentially in 3 parts. The primary objective for Part 1 is to determine the maximum tolerated dose of DES-1357 in participants with confirmed dMMR/MSI-H colorectal cancer (CRC). The primary objective for Part 2 is to assess the chronic tolerability and to identify the recommended Phase 2 dose (RP2D), to evaluate preliminary antitumor activity of the selected dose level of DES-1357, and to assess the pharmacokinetics (PK) and pharmacodynamics of DES-1357. The primary objective for Part 3 is to evaluate antitumor activity of the selected dose level of DES-1357.
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
- •Individuals must meet all of the following criteria to be included in the study:
- •Have read, understood, and signed the Informed Consent Form (ICF).
- •Male or female aged greater than or equal to (>=) 18 years at the time of signing the ICF.
- •Histologically or cytologically confirmed carcinoma of the colon and/or rectum deemed unresectable and/or with evidence of metastases, that has been cytologically or genetically confirmed as dMMR, and/or MSI-H.
- •Demonstrated disease progression and/or intolerability to prior treatment with any of the following: pembrolizumab, nivolumab (±ipilimumab), dostarlimab, chemotherapy (ie, FOLFOX, FOLFIRI, CAPEOX, or FOLFOXIRI [±bevacizumab]), encorafenib/cetuximab, trastuzumab-based combinations, KRAS inhibitor/EGFR inhibitor, regorafenib, or TAS-102 (±bevacizumab)
- •Measurable disease according to RECIST version 1.
- •Adequate organ function:
- •Absolute neutrophil count >=1,500 cells per/μL
- •Platelets >=100,000 cells/μL
- •Hemoglobin >=9 grams per deciliter (g/dL)
- •Total bilirubin less than or equal to (<=) 1.5*the Upper Limit of Normal (ULN) (<=3*ULN if attributable to known Gilbert's syndrome)
- •Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) <=5*ULN if liver metastasis present; if liver metastasis is not present, then AST/ALT <=3*ULN.
- •Measured creatinine clearance >=60 milliliter per minute (mL/min) per Cockcroft-Gault formula.
- •Prothrombin time (PT) or international normalized ratio and Partial Thromboplastin Time (PTT) <=1.5*ULN, unless receiving anti-coagulant therapy; Note: activated PTT can be used instead of PTT if it is the site's standard practice.
- •Have agreed to tissue sampling (biopsy [if available], baseline archival tissue, and/or fresh frozen tissue [if available]).
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or
- •An estimated life expectancy of at least 3 months based on investigator judgment.
- •Women of childbearing potential (WOCBP) and men must agree to use 2 highly effective methods of contraception or practice abstinence from 4 weeks before the first dose of DES-1357, throughout the study, and for 6 months after the last dose of DES-1357; men must refrain from donating or banking sperm during the same period.
- •Negative serum pregnancy test result at screening and on Cycle 1 Day 1 for WOCBP.
- •Female participants who are not WOCBP should meet at least 1 of the following criteria:
- •have undergone a documented hysterectomy, bilateral oophorectomy and/or bilateral salpingectomy; have medically confirmed ovarian failure, or achieved postmenopausal status (defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, or have a serum follicle-stimulating hormone level within the laboratory's reference range for postmenopausal women).
排除标准
- •Individuals meeting any of the following criteria at screening or baseline are ineligible to participate in this study:
- •Cytologically and/or genetically confirmed proficient mismatch repair (pMMR) and/or MSS.
- •Evidence of severe gastrointestinal malabsorption as determined by the investigator.
- •History or presence of dysphagia.
- •Symptomatic or clinically significant bowel obstruction, perforation, or high risk for obstruction as determined by the investigator.
- •Hypersensitivity to any component of DES-
- •Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than (>) 470 milliseconds (msec) based on triplicate 12-lead ECGs obtained at screening.
- •Has an active infection.
- •Has known Human Immunodeficiency Virus (HIV) infection that is not under control. All of these criteria are required: undetectable viral RNA, CD4+ counts/levels >=350, no history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic infection within the past 12 months, and clinically stable for at least 3 months on the same anti-HIV medications.
- •Has active or uncontrolled hepatitis B or C infection. Participants are eligible if they:
- •Have been curatively treated for hepatitis C virus infection as demonstrated clinically and by viral serologies
- •For hepatitis B, if the participant has a positive hepatitis B surface antigen result, viral load must be below 2000 international units per milliliter (IU/mL) in the absence of antiviral therapy for the last 12 weeks, and AST/ALT <=3*ULN
- •Uncontrolled diabetes as determined by the investigator.
- •Cardiovascular and/or cerebrovascular event in the prior 6 months before screening.
- •Has received prior treatment with a Werner Syndrome Helicase (WRN) inhibitor.
- •Has been diagnosed with Werner Syndrome.
- •Primary Central Nervous System (CNS) tumor/CNS metastasis.
- •Ongoing toxicities from prior anti-cancer therapy that have not resolved to baseline or grade <=1 (according to NCI-CTCAE version 6.0), except for alopecia and endocrinopathies that are stable under medication.
- •Is pregnant or breastfeeding, is planning to become pregnant during the study.
- •Is planning to donate/bank or retrieve eggs (ova, oocytes) or donate sperm during the study.
研究组 & 干预措施
Part 1: Dose Escalation
Participants will receive DES-1357 orally once daily (QD) in 21-day treatment cycles with a starting dose of 150 milligrams (mg). The planned escalation dose levels are 300 and 600 mg to identify the maximum tolerated dose (MTD) for DES-1357.
干预措施: DES-1357 (Drug)
Part 2: Dose Optimization - Dosing Schedule A
Participants will receive DES-1357 orally QD in Dosing Schedule A. The dosing schedules will be selected based on the escalation ranges of Part 1, to determine the RP2D for expansion in Part 3.
干预措施: DES-1357 (Drug)
Part 2: Dose Optimization - Dosing Schedule B
Participants will receive DES-1357 orally QD in Dosing Schedule B. The dosing schedules will be selected based on the escalation ranges of Part 1, to determine the RP2D for expansion in Part 3.
干预措施: DES-1357 (Drug)
Part 3: Dose Expansion
Participants will receive DES-1357 orally QD at the RP2D determined in Part 2 to further assess its efficacy and safety.
干预措施: DES-1357 (Drug)
结局指标
主要结局
Part 2: Area Under the Curve (AUC) of DES-1357
时间窗: Part 2: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days)
Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: Part 1: Cycle 1 (Cycle length=21 days)
A DLT is a toxicity that occurs during cycle 1 that meets the protocol-defined DLT criteria and is graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 6.0
Part 2: Incidence and Severity of Treatment- related Treatment Emergent Adverse Events (TEAEs) Through at least 3 Cycles of DES-1357
时间窗: Part 2: From the first dose of DES-1357 through at least 3 treatment cycles (Cycle length=21days)
A TEAE is defined as an AE with onset dates on or after the start of the study treatment or AEs that started prior to the start of the study treatment but worsened in severity after start of the study treatment.
Part 2: Best Overall Response (BOR)
时间窗: Part 2: From baseline through disease progression or end of treatment (EOT); tumor assessments every 8 weeks and at the EOT visit; assessed up to approximately 11 months
Best overall response is defined as the single best patient level response category (Complete Response \[CR\], Partial Response \[PR\], Stable Disease \[SD\], Progressive disease \[PD\], or Not Evaluable \[NE\]) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Part 2: Maximum Observed Concentration (Cmax) of DES-1357
时间窗: Part 2: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days)
Part 2: Time to Maximum Concentration (Tmax) of DES-1357
时间窗: Part 2: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days)
Part 2: Half Life (t1/2) of DES-1357
时间窗: Part 2: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days)
Part 2: Clearance (CL) of DES-1357
时间窗: Part 2: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days)
Part 2: Volume of Distribution (Vd) of DES-1357
时间窗: Part 2: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days)
Part 2: Change in Pharmacodynamic Markers Levels Following Treatment With DES-1357
时间窗: Part 2: Blood Samples: At Day 1 (pre-dose) of Cycles 1, 2, 3, 5, 7, and 9; Tumor tissue: At Screening and Cycle 1 Day 15 (±3 days, pre-dose) (Cycle length=21days)
Blood and tumor tissue samples will be collected for pharmacodynamic assessments. Biomarker evaluations may include circulating tumor Deoxyribonucleic Acid (ctDNA), carcinoembryonic antigen (CEA), Werner Syndrome Helicase (WRN) expression, phospho-H2AX expression, and other exploratory molecular analyses performed using immunohistochemistry and Ribonucleic Acid (RNA) sequencing methods.
Part 3: Objective Response Rate (ORR) by Independent Review Committee (IRC)
时间窗: Part 3: From baseline through EOT; tumor assessments every 8 weeks and at the EOT visit; assessed up to approximately 8 months
ORR is defined as the percentage of participants with a confirmed objective response (CR or PR) as determined per RECIST Version 1.1.
次要结局
- Part 1: Number of Participants With Treatment-related Adverse Events (AEs) Including TEAEs and Serious AEs(Part 1: From the first dose of DES-1357 through 30 days after the last dose (Cycle length=21 days)])
- Part 2: ORR According to RECIST Version 1.1(Part 2: From baseline through EOT; tumor assessments every 8 weeks and at the EOT visit; assessed up to approximately 11 months)
- Part 2 and Part 3: Disease Control Rate (DCR) According to RECIST Version 1.1(Part 2 and Part 3: From baseline through EOT; tumor assessments every 8 weeks and at the EOT visit; assessed up to approximately 11 months)
- Part 3: Duration of Response (DOR) According to RECIST Version 1.1(Part 3: From first documented objective response until first documented PD or death; assessed up to approximately 8 months)
- Part 1 and Part 3: Maximum Observed Concentration (Cmax) of DES-1357(Part 1 and Part 3: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days))
- Part 1 and Part 3: Time to Maximum Concentration (Tmax) of DES-1357(Part 1 and Part 3: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days))
- Part 1 and Part 3: Area Under the Curve (AUC) of DES-1357(Part 1 and Part 3: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days))
- Part 1 and Part 3: Half Life (t1/2) of DES-1357(Part 1 and Part 3: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days))
- Part 1 and Part 3: Clearance (CL) of DES-1357(Part 1 and Part 3: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days))
- Part 1 and Part 3: Volume of Distribution (Vd) of DES-1357(Part 1 and Part 3: Cycle 1 Day 1: predose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose; Cycle 1 Day 15: predose, 1, 2, 4, 8, 12 and 24 hours postdose; Cycle 1 Days 3, 5, and 21: at predose (Cycle length=21 days))
- Part 1 and Part 3: Change in Pharmacodynamic Markers Level of DES-1357(Part 1 and Part 3: Blood Samples: At Day 1 (pre-dose) of Cycles 1, 2, 3, 5, 7, and 9; Tumor tissue: At Screening and Cycle 1 Day 15 (±3 days, pre-dose) (Cycle length=21days))
- Part 2: ORR by an IRC According to RECIST Version 1.1(Part 2: From baseline through EOT; tumor assessments every 8 weeks and at the EOT visit; assessed up to approximately 11 months)
- Part 2: DCR by an IRC According to RECIST Version 1.1(Part 2: From baseline through EOT; tumor assessments every 8 weeks and at the EOT; assessed up to approximately 11 months)
- Part 2 and Part 3: Characterization of Biomarker Profiles Following Treatment With DES-1357(Part 2 and Part 3: Blood Samples: At Day 1 (pre-dose) of Cycles 1, 2, 3, 5, 7, and 9; Tumor tissue: At Screening and Cycle 1 Day 15 (±3 days, pre-dose) (Cycle length=21days))
- Part 3: European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ C30) Questionnaire(Part 3: Screening, and at Cycle 1 Days 1, 8, 15, 21 and at Day 21 for subsequent cycles up to 37 days after last dose of DES-1357 (Cycle length=21days))
- Part 3: Progression-Free Survival (PFS)(Part 3: From first dose of DES-1357 up to first documented disease progression or death; assessed for up to approximately 8 months)
- Part 3: Overall Survival (OS)(Part 3: From first dose of DES-1357 to date of death due to any cause; assessed for up to approximately 8 months)