A Phase I, Open Label Single-arm Two-part Study to Investigate Safety, Pharmacokinetics, and Preliminary Efficacy of Pan-RAF/MEK Glue NST-628 Oral Tablets in Subject With Solid Tumors Harboring Genetic Alterations in the MAPK Pathway and With Other Solid Tumors
概览
- 阶段
- 1 期
- 干预措施
- NST-628
- 疾病 / 适应症
- Oncology
- 发起方
- Nested Therapeutics, Inc
- 入组人数
- 230
- 试验地点
- 46
- 主要终点
- Part A and B: Evaluate the safety of NST-628 in patients with advanced solid tumors
- 状态
- 招募中
- 最后更新
- 12天前
概览
简要总结
This is a two-part Phase 1, open label, multi-center, single arm, non-randomized, multiple dose, safety, pharmacokinetic (PK) and preliminary efficacy study of single agent NST-628 in adult patients with MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options.
详细描述
The study includes two parts, a dose escalation part (Part A) followed by a dose expansion part (Part B). Part A will estimate the maximum tolerated dose (MTD) in dose escalation cohorts in patients with advanced solid tumors for whom no standard therapy is available in order to establish the recommended dose for expansion (RDE). Successive cohorts of subjects will receive escalating doses of NST-628 orally once daily in 28-day cycles. Bayesian Optimal Interval (BOIN) method will be used for dose escalation. Once MTD is reached or dose escalation is stopped prior to reaching MTD and provisional RDE selected, the provisional RDE level will be expanded. If warranted by dose/toxicity/anti-tumor activity observations, additional, lower dose level(s) may also be expanded. Part B of the study will include up to 6 cohorts of approximately up to 30 subjects each with select MAPK pathway mutant solid tumors enrolled at the RDE in order to explore benefit from treatment as suggested by preclinical findings and will better define the safety profile of NST-628 at the RDE. Additional safety information gathered in Part B may be used to modify the dose recommended for future studies. The end of the study is the last visit of the last subject.
研究者
入排标准
入选标准
- •Subjects are eligible to be included in the study only if all of the following criteria apply:
- •Subjects must be ≥18 years old (or of legal age of consent in the country in which the study is taking place) at the time of signing the informed consent.
- •Subjects who have a histologically or cytologically documented metastatic or locally advanced solid tumor, for which standard of care (SoC) therapy does not exist, no longer provides benefit, or is not tolerated by the subject, or the subject has been assessed by the Investigator as not being suitable for SoC therapy.
- •Part A: Subjects with any solid tumor with genetic alteration of or evidence of tumor dependence upon the RAS/MAPK pathway (subject to additional restrictions specified in the study protocol)
- •Part B: Subjects must be diagnosed with one of the following solid tumors harboring specified genetic alterations based on a validated local test:
- •i. Melanoma Cohorts:
- •Activating NRAS mutations
- •Select BRAF alterations
- •ii. Non-Melanoma Cohorts:
- •Solid tumors with NRAS activating mutations
排除标准
- •Subjects are excluded from the study if any of the following criteria apply:
- •Conditions interfering with oral intake of NST-628
- •Conditions interfering with intestinal absorption of an orally administered drug
- •A history or current evidence of significant retinal pathology leading to increased risk of RVO
- •A history or evidence of cardiovascular risk
- •Current or history within 6 months of planned Cycle 1 Day 1 of pneumonitis or interstitial lung disease (ILD)
- •Part B: prior treatment with any MEK or BRAF inhibitor
- •Untreated or symptomatic central nervous system (CNS) metastases
- •Chemotherapy, radiation, gene therapy, vaccine therapy, or anti-cancer antibodies / ADCs within 28 days of Cycle 1 Day 1
- •Targeted small molecule agents within 14 days or 5 half-lives of Cycle 1 Day 1
研究组 & 干预措施
Part A Dose Escalation and Part B Dose Expansion
Part A will evaluate the safety of NST-628 with advanced solid tumors and determine the recommended dose for expansion of NST-628. Part B will evaluate the objective tumor response rate in subjects with advanced solid tumors harboring specified genetic alterations receiving NST-628 and evaluate the safety of NST-628 in subjects with advanced solid tumors in cohorts defined below: i. Melanoma Cohorts 1. Activating NRAS mutations 2. Select BRAF alterations ii. Non-Melanoma Cohorts: 1. Solid tumors with NRAS activating mutations 2. Solid tumors with KRAS activating mutations 3. Solid tumors with select BRAF alterations 4. Glioma with BRAF alterations
干预措施: NST-628
结局指标
主要结局
Part A and B: Evaluate the safety of NST-628 in patients with advanced solid tumors
时间窗: Through study completion, an average of 1 year
Adverse effects
Part A: Determine the recommended dose for expansion of NST-628
时间窗: The first 28 days of treatment (DLTs)
Dose limiting toxicities (DLTs)
Part B: Evaluate objective tumor response rate
时间窗: Through study completion, an average of 1 year
Objective response per RECIST v. 1.1 or other response assessment tool standard for a given tumor type.
次要结局
- Part A: Evaluate objective tumor response rate(Through study completion, an average of 1 year)
- Part A and B: Evaluate progression free survival (PFS)(Through study completion, an average of 1 year)
- Part A and B: Characterize the pharmacokinetics of NST-628(Through study completion, an average of 1 year)
- Part A and B: Evaluate overall survival (OS)(Through study completion, an average of 2 years)