A Phase 1, Open-label, Multicenter, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of VVD-130037, a Kelch-like ECH Associated Protein 1 (KEAP1) Activator, in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 290
- 试验地点
- 50
- 主要终点
- Part 2 (Dose Expansion): Number of Participants With AEs, Serious Adverse Events (SAEs), and Clinical Laboratory Abnormalities
研究概览
简要总结
A FIH dose escalation and dose expansion study to evaluate VVD-130037 in participants with advanced solid tumors as a single agent, and in combination with docetaxel, paclitaxel, or pembrolizumab.
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
- •for Parts 1 and 2:
- •Histologically or cytologically confirmed metastatic or unresectable solid tumor.
- •Measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as assessed by the Investigator.
- •Have progressed on or after all prior standard-of-care therapies for metastatic disease.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Adequate organ and marrow function as defined in the protocol.
- •Additional Key Inclusion Criteria for Part 2:
- •Participants with squamous non-small cell lung cancer (sqNSCLC) with or without nuclear factor erythroid 2-related factor 2 (NRF2 [NFE2L2]) and/or cullin 3 (CUL3) mutations.
- •Participants with advanced sqNSCLC must be refractory to or have progressed on or after a platinum-based doublet regimen and an immune checkpoint inhibitor.
- •Participants with advanced head and neck squamous cell carcinoma (HNSCC) must have received prior treatment with platinum-based chemotherapy, an immune checkpoint inhibitor (for tumors with known programmed death-ligand 1 [PD-L1] expression, microsatellite instability-high, or mismatch repair deficiency, and an anti-epidermal growth factor receptor agent) (Combination Expansion Cohort).
- •Participants with advanced esophageal squamous cell carcinoma (ESCC) must have received prior treatment with platinum-based chemotherapy, an immune checkpoint inhibitor (for tumors with known PD-L1 expression) (Combination Expansion Cohort).
- •Participants with a known driver mutation, including activating epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, should have progressed after appropriate targeted treatment.
- •Participants with known human epidermal growth factor receptor 2 overexpression should have progressed after appropriate targeted treatment.
排除标准
- •for Parts 1 and 2:
- •Participant is known to have a mutation that has no expectation of benefit from VVD-
- •Current such mutations include the following:
- •KEAP1 nonsense mutation (any position)
- •KEAP1 frameshift mutation (any position)
- •Any unresolved toxicity Grade ≥2 per CTCAE version 5.0 from previous anticancer treatment.
- •Current or prior treatment with anti-epileptic medications for the treatment or prophylaxis of seizures.
- •History of seizure or condition that may predispose to seizure.
- •History or presence of central nervous system (CNS) metastases or spinal cord compression.
- •Uncontrolled arterial hypertension despite optimal medical management.
- •Risk factors for abnormal heart rhythm/QT prolongation as defined in the protocol.
- •History of the following cardiac diseases:
- •i) congestive heart failure (New York Heart Association [NYHA] Class >II), ii) unstable angina, iii) new onset angina within past 6 months, iv) myocardial Infarction within the past 6 months, v) clinically significant arrhythmias within past 6 months.
- •Any prior toxicity (Grade 3 or 4) related to immunotherapy leading to treatment discontinuation (Combination Expansion Cohort)
- •Medical history of (noninfectious) pneumonitis/interstitial lung disease (ILD), drug induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active pneumonitis/ILD (Combination Expansion Cohort)
研究组 & 干预措施
Part 2 (Dose Expansion): VVD-130037 and Docetaxel Combination Therapy
Participants will receive VVD-130037 at the RDE, orally, once or twice daily along with docetaxel IV infusion administered once every 3 weeks in 21-day treatment cycles during Part 2.
干预措施: Docetaxel (Drug)
Part 1 (Dose Escalation): VVD-130037 Single Agent
Participants will receive ascending doses of VVD-130037, orally, once or twice daily in 21-day treatment cycles during Part 1.
干预措施: VVD-130037 (Drug)
Part 1 (Dose Escalation): VVD-130037 and Docetaxel Combination Therapy
Participants will receive ascending doses of VVD-130037, orally, once or twice daily along with docetaxel intravenous (IV) infusion administered once every 3 weeks in 21-day treatment cycles during Part 1.
干预措施: VVD-130037 (Drug)
Part 1 (Dose Escalation): VVD-130037 and Docetaxel Combination Therapy
Participants will receive ascending doses of VVD-130037, orally, once or twice daily along with docetaxel intravenous (IV) infusion administered once every 3 weeks in 21-day treatment cycles during Part 1.
干预措施: Docetaxel (Drug)
Part 2 (Dose Expansion): VVD-130037 Single Agent
Participants will receive VVD-130037 at the recommended dose for expansion (RDE), orally, once or twice daily in 21-day treatment cycles during Part 2.
干预措施: VVD-130037 (Drug)
Part 2 (Dose Expansion): VVD-130037 and Paclitaxel Combination Therapy
Participants will receive VVD-130037 at the RDE, orally, once or twice daily along with paclitaxel IV infusion administered on Days 1, 8, and 15 of each 28-day treatment cycle during Part 2.
干预措施: Paclitaxel (Drug)
Part 1 (Dose Escalation): VVD-130037 and Paclitaxel Combination Therapy
Participants will receive ascending doses of VVD-130037, orally, once or twice daily along with paclitaxel IV infusion administered on Days 1, 8, and 15 of each 28-day treatment cycle during Part 1.
干预措施: VVD-130037 (Drug)
Part 1 (Dose Escalation): VVD-130037 and Paclitaxel Combination Therapy
Participants will receive ascending doses of VVD-130037, orally, once or twice daily along with paclitaxel IV infusion administered on Days 1, 8, and 15 of each 28-day treatment cycle during Part 1.
干预措施: Paclitaxel (Drug)
Part 2 (Dose Expansion): VVD-130037 and Docetaxel Combination Therapy
Participants will receive VVD-130037 at the RDE, orally, once or twice daily along with docetaxel IV infusion administered once every 3 weeks in 21-day treatment cycles during Part 2.
干预措施: VVD-130037 (Drug)
Part 2 (Dose Expansion): VVD-130037 and Paclitaxel Combination Therapy
Participants will receive VVD-130037 at the RDE, orally, once or twice daily along with paclitaxel IV infusion administered on Days 1, 8, and 15 of each 28-day treatment cycle during Part 2.
干预措施: VVD-130037 (Drug)
Experimental: Part 2 (Dose Expansion): VVD-130037 and Pembrolizumab Combination Therapy
Participants will first be evaluated in a safety-run in cohort to determine the RDE(s). Participants will then receive VVD-130037 at the RDE, orally, once or twice daily along with pembrolizumab IV infusion administered once every 3 weeks in 21-day treatment cycles during Part 2.
干预措施: VVD-130037 (Drug)
Experimental: Part 2 (Dose Expansion): VVD-130037 and Pembrolizumab Combination Therapy
Participants will first be evaluated in a safety-run in cohort to determine the RDE(s). Participants will then receive VVD-130037 at the RDE, orally, once or twice daily along with pembrolizumab IV infusion administered once every 3 weeks in 21-day treatment cycles during Part 2.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Part 2 (Dose Expansion): Number of Participants With AEs, Serious Adverse Events (SAEs), and Clinical Laboratory Abnormalities
时间窗: Up to approximately 4 years
Part 1 (Dose Escalation): Incidence and Severity of Dose-limiting Toxicities (DLTs) During DLT Observation Period
时间窗: Part 1: Single Agent and Docetaxel/Pembrolizumab Combination Therapy: From Day 1 to Day 21 of Cycle 1 [cycle length=21 days] and Part 1: Paclitaxel Combination Therapy: From Day 1 to Day 28 of Cycle 1 [cycle length=28 days]
Incidence and severity of DLTs will be assessed per DLT criteria set forth in the protocol based on adverse events (AEs) evaluated per National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Part 2 (Dose Expansion): Number of Participants With AEs, Serious Adverse Events (SAEs), and Clinical Laboratory Abnormalities
时间窗: Up to approximately 4 years
次要结局
- Part 2 (Dose Expansion): Recommended Phase 2 Dose (RP2D) of VVD-130037 as a Single Agent and in Combination with Docetaxel, Paclitaxel, or Pembrolizumab(Up to approximately 4 years)
- Part 2 (Dose Expansion): Duration of Response (DOR)(Up to approximately 4 years)
- Part 2 (Dose Expansion): Progression-free Survival (PFS)(Up to approximately 4 years)
- Part 2 (Dose Expansion): Disease Control Rate (DCR)(Up to approximately 4 years)
- Parts 1 and 2 (Dose Escalation and Expansion): Area Under the Plasma Concentration-time Curve (AUC) of VVD-130037(Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy))
- Parts 1 and 2 (Dose Escalation and Expansion): Maximum Observed Concentration (Cmax) of VVD-130037(Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy))
- Parts 1 and 2 (Dose Escalation and Expansion): Apparent Terminal Half-life (T1/2) of VVD-130037(Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy))
- Parts 1 and 2 (Dose Escalation and Expansion): QT/Corrected QT (QTc) Interval and Other Electrocardiogram (ECG) Parameters(Parts 1 and 2: Up to approximately 4 years)
- Part 1 (Dose Escalation): Number of Participants With AEs, SAEs, and Clinical Laboratory Abnormalities(Up to approximately 4 years)
- Part 1 (Dose Escalation): Number of Participants With AEs, SAEs, and Clinical Laboratory Abnormalities(Up to approximately 4 years)
- Part 2 (Dose Expansion): Recommended Phase 2 Dose (RP2D) of VVD-130037 as a Single Agent and in Combination with Docetaxel, Paclitaxel, or Pembrolizumab(Up to approximately 4 years)
- Part 2 (Dose Expansion): Overall Response Rate (ORR)(Up to approximately 4 years)
- Part 2 (Dose Expansion): Duration of Response (DOR)(Up to approximately 4 years)
- Part 2 (Dose Expansion): Progression-free Survival (PFS)(Up to approximately 4 years)
- Part 2 (Dose Expansion): Disease Control Rate (DCR)(Up to approximately 4 years)
- Parts 1 and 2 (Dose Escalation and Expansion): Area Under the Plasma Concentration-time Curve (AUC) of VVD-130037(Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy))
- Parts 1 and 2 (Dose Escalation and Expansion): Maximum Observed Concentration (Cmax) of VVD-130037(Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy))
- Parts 1 and 2 (Dose Escalation and Expansion): Apparent Terminal Half-life (T1/2) of VVD-130037(Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy))
- Parts 1 and 2 (Dose Escalation and Expansion): QT/Corrected QT (QTc) Interval and Other Electrocardiogram (ECG) Parameters(Parts 1 and 2: Up to approximately 4 years)