A Phase 1/2 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 in Patients With Advanced NSCLC and Other Solid Tumors (ALKOVE-1)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 840
- 试验地点
- 148
- 主要终点
- Dose limiting toxicities (DLTs) (Phase 1)
研究概览
简要总结
Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of neladalkib (NVL-655), determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ALK- positive (ALK+) NSCLC and other solid tumors.
Phase 1 will evaluate the overall safety and tolerability of neladalkib and will determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of neladalkib in patients with advanced ALK+ solid tumors.
Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of neladalkib at the RP2D. Secondary objectives will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) of neladalkib in patients with advanced ALK-positive NSCLC and other solid tumors.
A drug-drug interaction (DDI) sub-study will determine the effect of neladalkib on the pharmacokinetics of midazolam and repaglinide, as well as the effect of itraconazole on the pharmacokinetics of neladalkib, in patients with advanced ALK-positive NSCLC
详细描述
In Phase 2, study patients will be enrolled into 6 distinct cohorts:
- Cohort 2a: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
- Cohort 2b: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
- Cohort 2c: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
- Cohort 2d: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
- Cohort 2e: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
- Cohort 2f: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.
In the DDI sub-study, study patients will be enrolled into 2 distinct cohorts:
- Cohort G (DDI sub-study with midazolam and repaglinide): Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received ≥1 prior ALK TKI.
- Cohort H (DDI sub-study with itraconazole): Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received ≥1 prior ALK TKI.
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
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years, Phase 2 Cohort 2f only: Age ≥12 years and weighing >40 kg. DDI sub-study Cohorts G and H only: age 18-60 years, inclusive
- •Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation.
- •Phase 2 Cohorts except 2f: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement
- •Phase 2 Cohort 2f: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation detected by certified assay.
- •DDI sub-study cohorts: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement
- •DDI sub-study cohorts: Must have previously received ≥1 ALK TKI; no prior investigational agents targeting ALK; any number of prior chemotherapy and/or immunotherapy
- •Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1 Phase 2: Must have measurable disease according to RECIST 1.1
- •Adequate organ function and bone marrow reserve
排除标准
- •Patient's cancer has a known oncogenic driver alteration other than ALK.
- •Known allergy/hypersensitivity to excipients of NVL-
- •Major surgery within 4 weeks of the study entry
- •Ongoing or anticancer therapy
- •Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
研究组 & 干预措施
Phase 1 dose escalation
Neladalkib (NVL-655) oral daily dosing
干预措施: Neladalkib (NVL-655) (Drug)
Cohort 2c
Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
干预措施: Neladalkib (NVL-655) (Drug)
Cohort 2d
Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
干预措施: Neladalkib (NVL-655) (Drug)
Cohort 2e
Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
干预措施: Neladalkib (NVL-655) (Drug)
Cohort 2f
Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.
干预措施: Neladalkib (NVL-655) (Drug)
Cohort 2a
Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
干预措施: Neladalkib (NVL-655) (Drug)
Cohort 2b
Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
干预措施: Neladalkib (NVL-655) (Drug)
结局指标
主要结局
Dose limiting toxicities (DLTs) (Phase 1)
时间窗: Within the first 21 days of the first neladalkib (NVL-655) dose
Define the dose limiting toxicities (DLTs)
Recommended Phase 2 Dose (RP2D) (Phase 1)
时间窗: Within 21 days of last patient dosed during escalation
To determine the RP2D
Objective Response Rate (ORR) (Phase 2)
时间窗: 2-3 years after first patient dosed.
To determine ORR as assessed by BICR
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 1)
时间窗: Approximately 3 years
Incidence and severity of treatment-emergent adverse events (TEAEs)
次要结局
- Maximum plasma concentration, (Cmax) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Plasma concentration at the end of the dosing interval (Ctau) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Average plasma concentration (Cavg) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Time of maximum concentration (Tmax) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Area under the curve at the end of the dosing interval (AUCtau) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Area under the curve from time 0 to 24 (AUC0-24) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Area under the curve from time 0 to infinity (AUCinf) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Oral clearance (CL/F) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Volume of distribution (Vz/F) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Half-life (t1/2) of neladalkib (NVL-655)(Pre-dose and up to 24 hours post-dose)
- Objective response rate (ORR) (Phase 1)(2-3 years after first patient dosed)
- Duration of response (DOR)(2-3 years after first patient dosed)
- Clinical benefit rate (CBR)(2-3 years after first patient dosed)
- Time to response(Approximately 3 years)
- Progression-free survival (PFS)(2-3 years after first patient dosed)
- Overall survival (OS) (Phase 2)(Approximately 3 years)
- Number of participants with treatment-emergent adverse events, as assessed by CTCAE, V5.0 (Phase 2)(Approximately 3 years)
- Quality of life assessment(2-3 years after first patient dosed)