A Phase 1, First-in-Human, Open-Label Study to Evaluate the Safety, Tolerability, PK, and Preliminary Anti-tumor Activity of the Novel Orally Available CDK2 Inhibitor NKT3447 in Adults With Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 23
- 试验地点
- 8
- 主要终点
- Number of Participants with Dose Limiting Toxicity (DLT) events
研究概览
简要总结
The goal of the Dose Escalation phase of the study is to evaluate the safety, tolerability, and pharmacokinetics (PK) to determine the maximum tolerated dose (MTD) and/or preliminary recommended dose for expansion (RDE) of NKT3447 in adults with advanced or metastatic solid tumors. The goal of the Expansion phase of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), and the preliminary antitumor activity of NKT3447 in adult subjects with cyclin E1 (CCNE1) amplified ovarian cancer at the RDEs selected in Dose Escalation and to determine the preliminary recommended phase 2 dose (RP2D).
详细描述
This is a Phase 1/1b, first-in-human, open-label, multicenter study of NKT3447 in adults with advanced/ metastatic solid tumors. The study consists of 2 parts, a Dose Escalation phase and a Dose Expansion phase. Eligible patients must have confirmed advanced/metastatic solid tumors (as outlined below) with disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available standard treatment likely to improve the disease outcome in the judgment of the investigator.
Dose Escalation:
- Ovarian cancer
- Endometrial cancer
- Gastric cancer or gastroesophageal junction cancer
- Small cell lung cancer
- Triple-negative breast cancer (human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor negative)
- Estrogen receptor/progesterone-receptor positive (ER+/PR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (must have progressed following treatment with a CDK4/6 inhibitor, and not suitable for endocrine therapy)
- Other solid tumors with CCNE1 amplification as determined by next generation sequencing by local liquid or tissue biopsy.
Dose Expansion:
a. Platinum resistant or refractory ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least 1 platinum containing therapy with cyclin E amplification as determined by fluorescence in situ hybridization, quantitative polymerase chain reaction, or next-generation sequencing by local liquid or tissue biopsy.
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
盲法说明
Randomized for the Expansion Phase
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
- •Must have confirmed unresectable advanced/metastatic solid tumors (as outlined below) with disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available standard treatment likely to improve the disease outcome in the judgment of the Investigator.
- •Measurable disease per the RECIST v1.1
- •An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Able to swallow oral medications.
- •Dose Escalation(Part 1):
- •Ovarian cancer
- •Endometrial cancer
- •Gastric cancer or gastroesophageal junction cancer
- •Small cell lung cancer (SCLC)
- •Triple-negative breast cancer (human epidermal growth factor receptor 2 [HER2], estrogen receptor [ER], progesterone receptor negative)
- •ER/progesterone-receptor positive, HER2 negative breast cancer (must have progressed following treatment with a CDK4/6 inhibitor, and not suitable for endocrine therapy)
- •Other solid tumors with CCNE1 amplification as determined by NGS by local liquid or tissue biopsy.
- •Dose Expansion (Part 2):
- •a. Platinum resistant or refractory ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least 1 platinum containing therapy with CCNE1 amplification as determined by NGS by local liquid or tissue biopsy.
- •Measurable disease per the RECIST v1.1
- •An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- •Able to swallow oral medications.
排除标准
- •Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.
- •History of another malignancy with exceptions
- •Visceral crisis with life-threatening complications, lymphangitic spread, CNS metastasis and/or carcinomatous meningitis
- •Failed to recover from effects of prior anticancer treatment therapy to baseline or Grade ≤ 1 severity (per CTCAE)
- •Clinically active interstitial lung disease
- •History of uveitis, retinopathy or other clinically significant retinal disease
- •Has known human immunodeficiency virus (HIV), active hepatitis B or C infection
- •Prior CDK2 inhibitor
- •Major surgery within 2 months or minor surgery within 10 days before the first dose of NKT3447
研究组 & 干预措施
Dose Escalation
Dose escalation will assess the safety, efficacy, and PK/PD data of oral dosing NKT3447 at increasing dosage levels to determine the MTD and/or preliminary RDEs.
干预措施: NKT3447 (Drug)
Dose Expansion
Dose expansion will include 2 RDEs selected to determine the preliminary antitumor activity and the RP2D.
干预措施: NKT3447 (Drug)
结局指标
主要结局
Number of Participants with Dose Limiting Toxicity (DLT) events
时间窗: 28 days
DLTs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5 .0.
Objective Response Rate (ORR)
时间窗: 1 year
ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as determined by the Investigator
次要结局
- Progression-free survival (PFS)(2 years)
- Duration of Response (DOR)(2 years)
- Disease control rate(1 year)
- Overall Survival (OS)(2 years)
- Time to Response (TTR)(1 year)
- Number of Participants with Adverse Events(2 years)
- Maximum observed plasma concentration (Cmax) of NKT3447(1 month)
- Time to maximum observed plasma concentration of NKT3447 (Tmax)(1 month)
- Observed trough concentration of NKT3447 (Ctrough)(88 weeks)
- Area under the plasma concentration-time curve (AUC0-t) of NKT3447(1 month)
- Apparent clearance (CL/F)(1 month)
- Apparent volume of distribution (V/F)(1 month)
- Half-life (t1/2)(1 month)
- Accumulation ratio (AR)(1 month)